U.S. patent number 5,994,362 [Application Number 08/459,063] was granted by the patent office on 1999-11-30 for method of treatment for prostatic cancer.
This patent grant is currently assigned to Merck & Co., Inc.. Invention is credited to Glenn J. Gormley, Elizabeth Stoner.
United States Patent |
5,994,362 |
Gormley , et al. |
November 30, 1999 |
Method of treatment for prostatic cancer
Abstract
Disclosed is a new treatment for men with prostatic cancer
involving combination therapy of a 5.alpha.-reductase inhibitor,
i.e., a 17.beta.-substituted 4-azasteroid, a 17.beta.-substituted
non-azasteroid, 17.beta.-acyl-3-carboxyandrost-3,5-diene,
benzoylaminophenoxybutanoic acid derivative, fused benz(thio)amide
or cinnamoylamide derivative, aromatic 1,2-diethers or thioethers,
aromatic ortho acylaminophenoxy alkanoic acids, ortho
thioalkylacylamino-phenoxy alkanoic acids, pharmaceutically
acceptable salts and esters thereof, and particularly finasteride,
in combination with an antiandrogen, i.e. flutamide. Pharmaceutical
compositions useful for treatment are also disclosed.
Inventors: |
Gormley; Glenn J. (Westfield,
NJ), Stoner; Elizabeth (Westfield, NJ) |
Assignee: |
Merck & Co., Inc. (Rahway,
NJ)
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Family
ID: |
26789376 |
Appl.
No.: |
08/459,063 |
Filed: |
June 2, 1995 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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094950 |
Dec 27, 1993 |
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846154 |
Mar 11, 1992 |
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Current U.S.
Class: |
514/284;
514/522 |
Current CPC
Class: |
A61K
31/58 (20130101); A61K 31/192 (20130101) |
Current International
Class: |
A61K
31/58 (20060101); A61K 31/192 (20060101); A61K
31/185 (20060101); A61K 031/44 (); A61K
031/275 () |
Field of
Search: |
;514/284,522 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0 200 859 |
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Dec 1986 |
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EP |
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0 285 383 |
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May 1988 |
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EP |
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WO 92/00010 |
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Sep 1992 |
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WO |
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Other References
Labrie et al., Endocrinology 128(3) 1991, pp. 1673-1675,
"Combination of an antiandrogen and a 5alpha-reductase inhibitor" .
.
Andriole et al., The Prostate 10 (1987), pp. 189-197, "The effect
of 4MA, a potent inhibitor of 5alpha-reductase, on the growth of
androgen-responsive human genitourinary tumors . . . ". .
Liang et al., J. of Biol. Chem., 256(15), 1981, pp. 7998-8005,
"Inhibition of 5alpha-reductase, receptor binding, and nuclear
uptake of androgens in the prostate . . . ". .
Petrow et al, Steroids 38(2), 1981, pp. 121-140, "Prostatic cancer.
I. 6-methylene-4-pregnen-3-ones as irreversible inhibitors of rat
prostatic . . . ". .
Ito et al, J. Pharm. Pharmacol. 41 (1989), pp. 488-489, "A new
approach to prostate cancer". .
Kadohama et al., JNCL, vol. 74(2), 1984, pp. 475-486, "Retardation
of prostate tumor progression in the noble rat by
4-methyl-4-aza-steroidal inhibitors of 5alpha-reductase". .
Raynaud et al., Bull. Cancer (Paris), vol. 73(1), 1986, pp. 36-46,
"Cancer de la prostate" Bases biologiques pour l'emploi d'un
antiandrogene dans le traitement. .
Petrow et al., The Prostate, vol. 9, 1986, pp. 343-361, "The
dihydrotestosterone (DHT) hypothesis of prostate cancer and its
therapeutic implications". .
Petrow et al., The Prostatic Cell: Structure and Function, Part B,
(1981), pp. 283-296, "Studies on a 5alpha-reductase inhibitor and
their therapeutic implications". .
Sandberg et al., Progress in Cancer Research and Therapy, vol. 31
(1984), pp. 477-489, "Enzymatic and receptor systems as targets for
therapy of prostatic cancer". .
Isaacs et al., The Prostate, 1989, pp. 33-40, "Experimental studies
on optimal therapy for prostatic cancer". .
Stone et al., The Prostate, 1986, pp. 311-318, "Estrogen formation
in human prostatic tissue from patients with and without benign
prostatic hyperplasia". .
Olea et al., Endocrinology 126(3), 1990, pp. 1457-1463, "The
proliferative effect of 'anti-androgens' on the androgen-sensitive
human prostate cell line LNCaP". .
Furr et al., UK. European Urology (1990) 18 Suppl., 3, pp. 2-9.
.
Pode et al., European Urology (1990) 18 Suppl 1, p. 177..
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Primary Examiner: Goldberg; Jerome D.
Attorney, Agent or Firm: Fitch; Catherine D. Winokur;
Melvin
Parent Case Text
This is a continuation of application Ser. No. 08/094,950 filed
Dec. 27, 1993 now abandoned which is a continuation of application
Ser. No. 07/846,154, filed Mar. 11, 1992 now abandoned.
Claims
What is claimed is:
1. A method of treating prostatic cancer in patients who are in
need of such treatment comprising the step of administering to such
patients enhanced therapeutically effective amounts of the
5.alpha.-reductase inhibitor finasteride or a pharmaceutically
acceptable ester or salt thereof in combination with the
antiandrogen casodex.
2. A method according to claim 1 of treating prostatic cancer in
patients who are in need of such treatment comprising the step of
administering to such patients enhanced therapeutically effective
amounts of the 5.alpha.-reductase inhibitor finasteride or a
pharmaceutically acceptable ester or salt thereof, in combination
with the antiandrogen casodex, wherein the combination is more
effective than the use of either the 5.alpha.-reductase inhibitor
or antiandrogen by itself.
3. A pharmaceutical composition for the treatment of prostatic
cancer comprising enhanced therapeutically effective amounts of the
5.alpha.-reductase inhibitor finasteride and the antiandrogen
casodex.
Description
BACKGROUND OF THE INVENTION
This invention relates to a new method of treatment for patients,
i.e. men having prostatic cancer, which treatment involves a
combination therapy of administering therapeutically effective
amounts of a 5.alpha.-reductase inhibitor in combination with an
antiandrogenic agent.
BACKGROUND OF THE INVENTION
Prostate cancer is the second most common cancer occurring among
males and the third leading cause of cancer deaths in males over
50. Most prostate cancers exhibit some degree of androgen
dependence. Eunuchs do not develop prostate cancer suggesting a
hormonal role for prostate cancer. Charles Huggins, et al.,
established conclusively that androgens play a pivotal role in
prostate cancer and that surgical or medical castration of affected
men often causes at least temporary regression of the tumor. (See
Cancer Research 1, pp. 293-297 (1941).)
It is known that testosterone (T) is secreted by the testes and
adrenal glands but can undergo a 5.alpha.-reductase mediated
conversion to dihydrotestosterone (DHT) in peripheral sites
including the liver, skin, and prostate. DHT is preferentially
bound by the nucleus of prostatic cells and so it is generally
accepted that DHT, rather than T, is the androgen required by the
prostate for its growth and function.
Finasteride,
17.beta.(N-t-butyl)carbamoyl-4-aza-5.alpha.-androst-1-en-3-one was
developed as the culmination of a search for compounds which would
inhibit 5.alpha.-reductase and thus have the potential for being
useful against benign prostatic hyperplasia. Finasteride is a
4-azasteroid and a competitive inhibitor of the enzyme. It shows no
affinity for the androgen receptor and so would not be expected to
interfere with the binding and action of T in those tissues, such
as muscle, which respond to T.
However, these above studies do not provide information on whether
finasteride is an effective and safe agent in the treatment of
prostatic cancer.
There are several methods described in the prior art for treating
prostatic cancer and related prostatic disorders, for example:
U.S. Pat. No. 4,472,382 (Labrie, et al.), discloses that prostate
adenocarcinoma, benign prostate hypertrophy and hormone-dependent
mammary tumors may be treated with various LH-RH agonists and that
prostate adenocarcinoma and benign hypertrophy may be treated by
use of various LH-RH agonists and an antiandrogen.
U.S. Pat. No. 4,659,695 (Labrie), discloses a method of treatment
of prostate cancer in susceptible male animals including humans
whose testicular hormonal secretions are blocked by surgical or
chemical means, e.g., by use of an LH-RH agonist, e.g.,
[D-Trp.sup.6, des-Gly-NH.sub.2.sup.10 ]LH-RH ethylamide which
comprises administering an antiandrogen, e.g., flutamide in
association with at least one inhibitor of sex steroid
biosynthesis, e.g., aminoglutethimide and/or ketoconazole.
U.S. Pat. No. 3,995,060 (Neri, et al.), discloses methods of
preparing certain antiandrogens including 4'-substituted and
3',4'-disubstituted anilides, e.g. flutamide, and their use in
treating androgen-dependent or androgen-caused disease states, such
as prostatic andenocarcinoma, benign prostate hypertrophy,
hirsutism, and acne, in mammals, including man.
U.S. Pat. No. 4,895,715 (Neri, et al.), discloses methods for
treating androgen-dependent gynecomestia in patients being treated
for diseases such as benign prostatic hypertrophy involving the
combination therapy of an antiandrogen, i.e. flutamide with an
antiestrogen, or an aromatase inhibitor.
However, none of these methods suggest or employ a
5.alpha.-reductase inhibitor alone or in combination with another
agent.
In addition to DHT, there are other androgens such as testosterone
(T) which are also active in the prostate by participating in
binding to androgen receptors. It is known that antiandrogen
agents, i.e. the non-steroidal flutamide, being
4'-nitro-3'-trifluoromethyl-isobutyranilide, are effective as
competitive agents in binding to the androgen receptors, thus
blocking the adverse action of androgens in androgen-dependent
disease states. (See U.S. Pat. No. 3,995,060 to Neri, Supra.)
It is further known that, in the early stages of prostatic cancer
prostatic tumors are androgen-dependent for growth. One of the most
important androgens in this respect is dihydrotestosterone (DHT).
The production of DHT in the prostate by the enzymic action of
5.alpha.-reductase on testosterone can be blocked by the use of
e.g., 4-aza steroids, as 5.alpha.-reductase inhibitors, which are
known in the art. (See Merck U.S. Pat. No. 4,760,071.) Further, it
is believed that testosterone, also an androgen, may have
characteristics required by prostatic tumors.
Thus, the combined effect of a 5.alpha.-reductase inhibitor in
inhibiting DHT production in the prostate and the androgen receptor
blocking action of an antiandrogen, i.e. flutamide, will produce a
greater effect on suppressing the growth, spread and metastasis of
prostatic tumors then either agent by itself.
SUMMARY OF THE INVENTION
By this invention there is provided a method of treating prostatic
cancer patients who are in need of such treatment comprising the
step of administering in combination to such patients
therapeutically effective amounts of a 5.alpha.-reductase inhibitor
e.g. a 17.beta.-substituted 4-azasteroid, a 17.beta.-substituted
non-azasteroid, 17.beta.-acyl-3-carboxyandrost-3,5-diene,
benzoylaminophenoxybutanoic acid derivative, fused benz(thio)amide
or cinnamoylamide derivative, aromatic 1,2-diethers or thioethers,
aromatic ortho acylaminophenoxy alkanoic acids, ortho
thioalkylacylamino-phenoxy alkanoic acids, pharmaceutically
acceptable salts and esters thereof, and particularly finasteride
in combination with an antiandrogen.
BRIEF DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
In one preferred aspect, the present invention provides an
effective method of treating prostate cancer in patients in need of
such treating by administering therapeutically effective amounts of
the antiandrogen in association with a 5.alpha.-reductase inhibitor
or pharmaceutical composition thereof. The active compounds may be
administered together or in any order, as discussed
hereinafter.
By the term "patients in need of such treating" is meant "male
patients with functioning gonads who are being treated with a
5.alpha.-reductase inhibitor in a therapeutic program designed to
combat prostatic cancer and/or benign prostatic hyperplasia (BPH)
and are discovered to have a stage of cancer in which the prostatic
tumors are still androgen dependent.
The use of therapeutically effective amounts of the
5.alpha.-reductase inhibitor and the antiandrogen in accordance
with this invention effectively treats prostatic cancer and is more
effective than the use of either agent entirely by itself.
Typical suitable antiandrogens known in the art and useful and
included within the scope of this invention include nonsteroidal
antiandrogens such as the imidazolidines, especially
1-(3'-trifluoromethyl-4'nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione
(also called Anandron) described in U.S. Pat. No. 4,097,578;
4'-nitro-3-trifluoromethylisobutyranilide (also called flutamide)
described in U.S. Pat. No. 3,847,988, hydroxyflutamide described in
U.S. Pat. No. 3,875,229 and prodrug forms of hydroxyflutamide; the
N-(phenylalkanoyl)aniline derivatives disclosed in U.S. Pat. No.
4,386,080; the 3,4-disubstituted-branched-chain acylanilides
disclosed in U.S. Pat. No. 4,239,776 (A. T. Glen, et al.) and
specifically casodex (Imperial Chemical Industries), which is
N-[4-cyano-3-(trifluoromethyl)
phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-propionamide
disclosed in U.S. Pat. No. 4,636,505 (H. Tucker).
Representative compounds of the non-steroidal antiandrogens
described above are the following:
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-5-iminoimidazoline-2-one
;
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione;
ethyl
N-(4-nitro-3-trifluoromethylphenyl)-cyclopropylcarbimidate;
ethyl N-(4-nitro-3-trifluoromethylphenyl)-isobutyrimidate;
ethyl N-(4-iodo-3-trifluoromethylphenyl)-isobutyrimidate;
ethyl
N-(4-nitro-3-trifluoromethylphenyl)-2.3-dimethyl-butyrimidate;
ethyl
N-(4'-nitro-3'trifluoromethylphenyl)-2-methylbutyrimidate;
ethyl N-(4-bromo-3-trifluoromethylphenyl)-isobutyrimidate;
ethyl N-(4-nitrophenyl)-isobutyrimidate;
ethyl N-(4-chloro-3-trifluoromethylphenyl)-isobutyrimidate;
ethyl N-(3-bromo-4-nitrophenyl)-isobutyrimidate;
ethyl N-(3-chloro-4-nitrophenyl)-isobutyrimidate;
N-(4-Nitro-3-trifluoromethylphenyl) isobutyrchlorimidate;
4-Nitro-3-trifluoromethylisobutyrthioanilide;
Ethyl N-(4-nitro-3-trifluoromethylphenyl)-isobutyrimidate;
Methyl
N-(4-nitro-3-trifluoromethylphenyl)-2-hydroxyisobutyrimidate;
2-bromo-4'-nitro-3'-trifluoromethylisobutyranalide;
2-methoxy,2-fluoro-2-chloro-3'-trifluoromethylisobutyranilide;
2-iodo-4'-nitro-3'trifluoromethylisobutyranilide;
N-methyl-2-bromo-4'-nitro-3'-trifluoromethylisobutyranilide;
N-ethyl-2-bromo-4'-nitro-3'-trifluoromethylisobutyranilide;
N-propyl-2-bromo-4'-nitro-3'-trifluoromethylisobutyranilide;
N-butyl-2-bromo-4'-nitro-3'-trifluoromethylisobutyranilide;
2-hydroxy-4'-nitro-3'-trifluoromethylisobutyranilide;
3',4'dinitro-2-hydroxyisovaleranilide;
4'-chloro-2-hydroxy-3'-trifluoromethylcyclobutylcarbanilide;
3'-chloro-2-hydro-4'-iodocyclopropylcarbanilide;
3'-bromo-2-hydroxy-3-methyl-4'-nitrovaleranilide;
2-hydroxy-3'-iodo-4'-trifluoromethylisobutyranilide;
2,3-dimethyl-2-hydroxy-3'-methyl-4'-nitrovaleranilide;
3'-acetyl-2,3-dimethyl-2-hydroxy-4'-iodovaleranilide;
3'-acetyl-2,3-dimethyl-2-hydroxy-4'-nitrovaleranilide;
2-hydroxy-3'-methoxy-4'nitroisobutyranilide;
3'-ethyl-2-hydroxy-4'-trifluoromethylisobutyranilide;
2,3-dimethyl-2-hydroxy-4'-nitro-3'-trifluoromethylthiovaleranilide;
4'-chloro-2-hydroxy-3'-propylisobutyranilide;
3'-bromo-2,3-dimethyl-2-hydroxy-4'-trifluoromethylcyclopropylcarbanilide;
2-hydroxy-4'-nitrobutyranilide;
2-hydroxy-3'-nitro-4'-bromoisobutyranilide;
4'-chloro-2-hydroxy-3'-iodoisovaleranilide;
2-bromo-4'-nitrocyclopropylcarbanilide;
2,3-dimethyl-2-hydroxy-3'-propionyl-4'-trifluoromethylbutyranilide;
2,3-dimethyl-2-hydroxy-3'-propionyl-4'-nitrobutyranilide;
2-hydroxy-4'-trifluoromethylisobutyranilide;
2-hydroxy-4'-nitro-3'-trifluoromethylisovaleranilide;
2-hydroxy-2-methyl-4'-nitro-3'-trifluoromethylbutyranilide;
2-hydroxy-3'-4'-dichloroisobutyranilide;
2-hydroxy-3'-4'-diiodoisobutyranilide;
3'-fluoro-2-hydroxy-4'-nitroisobutyranilide;
2-hydroxy-4'-chloro-3'-trifluoromethylisobutyranilide;
2-hydroxy-4'-nitroisobutyranilide;
2-ethyl-2-hydroxy-4'-nitro-3'-trifluoromethylbutyranilide;
3'-bromo-2-hydroxy-4'-nitroisobutyranilide;
2,3-dimethyl-2-hydroxy-4'-nitro-3'-trifluoromethylbutyranilide;
2-hydroxy-N-methyl-4'-nitro-3'-trifluoromethylisobutyranilide;
4'-chloro-2-hydroxy-N-methyl-3'-trifluoromethylisobutyranilide;
4'-bromo-2-hydroxy-3'-trifluoromethylisobutyranilide;
2,3-dimethyl-2-hydroxy-4'-nitro-3'-trifluoromethylbutyranilide;
2-hydroxy-N-methyl-4'-nitro-3'-trifluoromethylisobutyranilide;
2-acetoxy-4'-nitro-3'-trifluoromethylisobutyranilide;
2-methoxy-4'-nitro-3'-trifluoromethylisobutyranilide;
2-valeryloxy-4'-nitro-3'-trifluoromethylisobutyranilide;
2-hydroxy-3'-bromo-4'-nitroisobutyranilide;
2-hydroxy-4'-bromo-3'-trifluoromethylisobutyranilide;
2-acetoxy-4'-bromo-3'-trifluoromethylisobutyranilide;
3'-bromo-2-chloro-4'-nitroisobutyranilide;
2-bromo-4'-nitro-3'-trifluoromethylisobutyranilide;
N-methyl-2-methoxy-4'-nitro-3'-trifluoromethylisobutyranilide;
4'-bromo-2-chloro-3'-trifluoromethylisobutyranilide;
2-chloro-4'-iodo-3'-trifluoromethylisobutyranilide;
2-acetoxy-4'-bromo-3'-trifluoromethylisobutyranilide;
3'-chloro-2-hydroxy-4'-nitroisobutyranilide;
4'-bromo-2-methoxy-3'-trifluoromethylisobutyranilide;
2-chloro-4'-nitro-3'-trifluoromethylisobutyranilide;
2-hydroxy-4'-chloro-3'-trifluoromethylisobutyranilide;
2-hydroxy-4'-nitro-3'-trifluoromethylcyclopropylcarbanilide;
2-hydroxy-4'-iodo-3'-trifluoromethylcyclopropylcarbanilide;
2,3-dimethyl-2-hydroxy-4'-nitro-3'-trifluoromethylbutyranilide;
2-hydroxy-4'-nitro-3'-trifluoromethylisovaleranilide;
4'-bromo-2-hydroxy-3'-trifluoromethylisobutyranilide;
2'-hydroxy-4'-nitroisobutyranilide;
4'-chloro-2-hydroxy-3'-trifluoromethylisobutyranilide;
3'-bromo-2-hydroxy-4'-nitroisobutyranilide;
3'-chloro-2-hydroxy-4'-nitroisobutyranilide;
2-chloro-4'-nitro-3'-trifluoromethyl-cyclopropylcarbanilide;
2-chloro-4'nitro-3'-iodo-3'-trifluoromethylbutyranilide;
2-chloro-4'-nitro-3'-trifluoromethylcyclopropylcarbanilide;
2-chloro-4'-nitro-3'-trifluoromethyl-isobutyranilide;
2-chloro-2,3-dimethyl-4'iodo-3'-trifluoromethylbutyranilide;
2-chloro-4'-nitro-3'-trifluoromethylisovaleranilide;
4'-bromo-2-chloro-3'-trifluoromethylisovaleranilide;
4'-bromo-2-chloro-3'-trifluoromethylisobutyranilide;
2-chloro-4'-nitroisobutyranilide;
2,4'-dichloro-3'-trifluoromethylisobutyranilide;
3'-bromo-2-chloro-4'-nitroisobutyranilide;
2,3'-dichloro-4'-nitroisobutyranilide;
4'-Nitro-3'-trifluoromethyl-2-valeryloxyisobutyranilide;
3,4-dichloro-N-(2-hydroxy-2-p-nitrophenylpropionyl)aniline;
4-nitro-3-trifluoromethyl-N-(2-hydroxy-2-p-nitro-phenylpropionyl)aniline;
4-cyano-3-trifluoromethyl-N-(2-hydroxy-2-p-nitro-phenylpropionyl)aniline;
3-chloro-4-nitro-N-(2-hydroxy-2-p-nitrophenylpropionyl)aniline;
3-chloro-4-methylsulphonyl-N-(2-hydroxy-2-p-nitro-phenylpropionyl)aniline;
4-nitro-3-trifluoromethyl-N-(2-hydroxy-2-p-trifluoromethylphenylpropionyl)a
niline;
3-chloro-4-nitro-N-(2-hydroxy-2-p-trifluoromethylphenylpropionyl)aniline;
4-nitro-3-trifluoromethyl-N-(2-p-cyanophenyl-2-hydroxypropionyl)aniline;
4-nitro-3-trifluoromethyl-N-(2-p-fluorophenyl-2-hydroxypropionyl)aniline;
4-nitro-3-trifluoromethyl-N-(2-hydroxy-2-p-methylsulphinylphenylpropionyl)a
niline;
3,4-dichloro-N-(2-hydroxy-2-p-methylsulphinylphenylpropionyl)aniline;
3,4-dichloro-N-(2-p-acetylphenyl-2-hydroxypropionyl)aniline;
3,4,5,-trichloro-N-(2-hydroxy-2-p-nitrophenylpropionyl)aniline;
2-chloro-4-nitro-N-(2-hydroxy-2-p-nitrophenylpropionyl)aniline;
N-(2-methoxy-2-p-nitrophenylpropionyl)-4-nitro-3-trifluoromethylaniline;
N-(2-n-butoxy-2-p-nitrophenylpropionyl)-4-nitro-3-trifluoromethylaniline;
4-nitro-3-trifluoromethyl-N-(2-p-nitrophenylpropionyl)aniline;
4-nitro-3-trifluoromethyl-N-(2-hydroxy-2-p-methanesulphinylphenylpropionyl)
aniline;
4-nitro-3-trifluoromethyl-N-(2-hydroxy-2-p-methanesulphonylphenylpropionyl)
aniline;
4-nitro-3-trifluoromethyl-N-(3-chloro-2-hydroxy-2-p-nitrophenylpropionyl)an
iline;
3,4-dichloro-N-(3-chloro-2-hydroxy-2-nitrophenylpropionyl)aniline;
3-chloro-4-cyano-N-(3-chloro-2-hydroxy-2-p-nitrophenylpropionyl)aniline;
3,4-dichloro-N-(2-hydroxy-2-p-methoxycarbonylphenylpropionyl)aniline;
5-methyl-5-p-nitrophenyl-3-(4-nitro-3-trifluoromethylphenyl)oxazolidine-2,4
-dione;
3,4-dicyanoisobutyrylanilide;
3,4-dicyano-(2-hydroxy-2-methylpropionyl)anilide;
3,4-dicyano-N-methylisobutyrylanilide;
3,4-dicyano-(2-methoxy-2-methylpropionyl)anilide;
4-cyano-3-trifluoromethyl-(2-hydroxy-2-methylpropionyl)anilide;
3,4-dicyano-(2-acetoxy-2-methylpropionyl)anilide;
3,4-dicyano-(2-hydroxy-2-methylpropionyl)anilide;
3,4-dicyano-(cyclopropanecarbonyl)anilide;
3-cyano-4-nitro-(2-hydroxy-2-methylpropionyl)anilide;
3,4-dicyano-N-methylisobutyranilide;
3,4-dicyano-N-ethylisobutyranilide;
N-butyl-3,4-dicyanoisobutyranilide;
3,4-dicyano-(2-decanoyloxy-2-methylpropionyl)anilide;
3,4-dicyano-(2-hydroxy-2-methylpropionyl)anilide;
3-chloro-4-cyano-N-(3-ethylthio-2-hydroxy-2-methylpropionyl)aniline;
3-chloro-4-cyano-N-(3-ethylsulphonyl-2-hydroxy-2-methylpropionyl)aniline;
4-cyano-3-trifluoromethyl-N-(2-hydroxy-2-methyl-3-phenylsulphonylpropionyl)
aniline;
4-cyano-3-trifluoromethyl-N-(3-ethylsulphonyl-2-hydroxy-2-methylproionyl)an
iline;
4-nitro-3-trifluoromethyl-N-(2-hydroxy-3-phenylsulphonyl-2-methylpropionyl)
aniline;
4-nitro-3-trifluoromethyl-N-(3-ethylsulphonyl-2-hydroxy-2-methylpropionyl)a
niline;
3-chloro-4-nitro-N-(2-hydroxy-3-phenylthio-2-methylpropionyl)aniline;
4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(thiazol-2-ylthio)propion
yl]aniline;
4-nitro-3-trifluoromethyl-N-[3-allylthio-2-hydroxy-2-methylpropionyl)anilin
e;
4-nitro-3-trifluoromethyl-N-(3-p-fluorophenylthio-2-hydroxy-2-methylpropion
yl)aniline;
4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(pyrid-2-ylthio)propionyl
]aniline;
4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(5-methyl-1,3,4-thiadiazo
l-2-ylthio)propionyl)aniline;
4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(4-methylthiazol-2-ylthio
)propionyl]aniline;
4-nitro-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(pyrid-2-ylsulphonyl)prop
ionyl]aniline;
4-nitro-3-trifluoromethyl-N-(3-p-fluorophenyl-sulphonyl-2-hydroxy-2-methylp
ropionyl)aniline;
4-cyano-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(thiazol-2-ylthio)propion
yl]aniline;
4-cyano-3-trifluoromethyl-N-[2-hydroxy-2-methyl-3-(pyrid-2-ylthio)propionyl
]aniline;
4-cyano-3-trifluoromethyl-N-(2-hydroxy-2-methyl-3-methylthiopropionyl)anili
ne;
4-cyano-3-trifluoromethyl-N-(3-p-fluorophenylthio-2-hydroxy-2-methylpropion
yl)aniline; and
4-cyano-3-trifluoromethyl-N-(3-p-fluorophenyl-sulphonyl-2-hydroxy-2-methylp
ropionyl)aniline, and the like.
Typical suitable steroidal antiandrogens known in the art include
cyproterone,
6-chloro-1,2-dihydro-17-(acetyl)-3'H-cyclopropa[1,2]-pregna-1,4,6-triene-3
,20-dione, available under the tradename of Androcur from Schering
A. G., W. Berlin. See U.S. Pat. No. 3,234,093.
The use of pure antiandrogens such as flutamide is preferred. By
the term "pure antiandrogen" is meant an antiandrogen which is
devoid of any androgenic, estrogenic, antiestrogenic,
progestational, antiprogestational, angonadotrophic or
adrenocortical activity.
Typical 5.alpha.-reductase inhibitors known in the art include the
4-aza steroids developed by Merck. (See U.S. Pat. No. 4,377,584 to
Rasmusson, et al; U.S. Pat. No. 4,220,735 to Rasmusson, et al.;
U.S. Pat. No. 4,845,104 to Carlin, et al; U.S. Pat. No. 4,760,071
to Rasmusson, et al., which discloses finasteride, being
17.beta.-(N-t-butyl)carbamoyl-4-aza-5.alpha.-androst-1-en-3-one,
known by its trademark as PROSCAR*; U.S. Pat. No. 4,732,897 to
Cainelli, et al.; U.S. Pat. No. 4,859,681 to Rasmusson, et al.; EPO
Publn. 0 155 076; EPO Publn. 0 004 949; and EPO Publn. 0 314
189.
Preferred are where the 4-aza steroid has the formula: ##STR1##
wherein the dotted line represents a double bond when present,
R.sup.1 and R.sup.3 are independently hydrogen, methyl or
ethyl,
R.sup.2 is a hydrocarbon radical selected from straight or branched
chain substituted or unsubstituted alkyl, cycloalkyl, or aralkyl of
from 1-12 carbons or monocyclic aryl optionally containing 1 or
more lower alkyl substituents of from 1-2 carbon atoms and/or 1 or
more halogen substituents,
R' is hydrogen or methyl,
R" is hydrogen or .beta.-methyl,
R'" is hydrogen, .alpha.-methyl or .beta.-methyl, and
pharmaceutically acceptable salts or esters thereof.
A preferred embodiment of the compound of formula I applicable in
the process of our invention is represented by the formula:
##STR2## wherein R.sup.1 is hydrogen, methyl or ethyl, and
R.sup.2 is branched chain alkyl, cycloalkyl, aralkyl of from 4-12
carbons,
phenyl, optionally substituted by methyl, chloro or fluoro,
substituted or unsubstituted 1-, 2-adamantyl, 1-,
2-adamantylmethyl, 1-, 2- or 7-norbornanyl, 1-, 2- or
7-norbornanymethyl.
Representative compounds of the present invention include the
following:
17.beta.-(N-tert-amylcarbamoyl-4-aza-5.alpha.-androst-1-en-3-one,
17.beta.-(N-tert-hexylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one,
17.beta.-(N-tert-butylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one,
17.beta.-(N-isobutylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one,
17.beta.-(N-tert-octylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one,
17.beta.-(N-octylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one,
17.beta.-(N-1,1-diethylbutylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one,
17.beta.-(N-neopentylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one,
17.beta.-(N-2-adamantylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one,
17.beta.-(N-1-adamantylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one,
17.beta.-(N-2-norbornylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one,
17.beta.-(N-1-norbornylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one,
17.beta.-(N-phenylcarbamoyl)-4-aza-4-methyl-5.alpha.-androst-1-en-3-one,
17.beta.-(N-benzylcarbamoyl)-4-aza-4-methyl-5.alpha.-androst-1-en-3-one,
17.beta.-(N-tert-amylcarbamoyl-4-aza-4-methyl-5.alpha.-androst-1-en-3-one,
17.beta.-(N-tert-hexylcarbamoyl)-4-aza-4-methyl-5.alpha.-androst-1-en-3-one
17.beta.-(N-tert-butylcarbamoyl)-4-aza-4-methyl-5.alpha.-androst-1-en-3-one
17.beta.-(N-isobutylcarbamoyl)-4-aza-4-methyl-5.alpha.-androst-1-en-3-one,
17.beta.-(N-tert-octylcarbamoyl)-4-aza-4-methyl-5.alpha.-androst-1-en-3-one
17.beta.-(N-1,1,3,3-tetramethylbutylcarbamoyl)-4-aza-5.alpha.-androst-1-en-
3-one,
17.beta.-(N-octylcarbamoyl)-4-aza-4-methyl-5.alpha.-androst-1-en-3-one,
17.beta.-(N-1,1-diethylbutylcarbamoyl)-4-aza-4-methyl-5.alpha.-androst-1-en
-3-one,
17.beta.-(N-neopentylcarbamoyl)-4-aza-4-methyl-5.alpha.-androst-1-en-3-one,
17.beta.(N-1-adamantylcarbamoyl)-4-aza-5.alpha.-androstan-3-one;
17.beta.(N-1-adamantylcarbamoyl)-4-methyl-4-aza-5.alpha.-androst-1-en-3-one
;
17.beta.(N-1-adamantylcarbamoyl)-4-methyl-4-aza-5.alpha.-androstan-3-one;
17.beta.-(N-1-adamantylmethylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(N-2-adamantylcarbamoyl)-4-aza-5.alpha.-androstan-3-one;
17.beta.-(N-methyl-N-2-adamantylcarbamoyl)-4-methyl-4-aza-androstan-3-one;
17.beta.-(N-2-adamantylcarbamoyl)-4-methyl-4-aza-5.alpha.-androstane-3-one;
17.beta.-(N-2-adamantylcarbamoyl)-4-methyl-4-aza-5.alpha.-androst-1-en-3-on
e;
17.beta.-(N-methyl-N-2-adamantyl)carbamoyl-4-methyl-4-aza-androst-1-en-3-on
e;
17.beta.-(N-(3-methyl)-1-adamantyl-carbamoyl)-4-aza-4-methyl-5.alpha.-andro
st-an-3-one;
17.beta.-(N-exo-2-norbornanylcarbamoyl)-4-aza-4-methyl-5.alpha.-androst-1-e
n-3-one;
17.beta.-(N-exo-2-norbornanylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one;1
7.beta.-(N-2-adamantylcarbamoyl)-4-aza-5.alpha.-androst-en-3-one;
17.beta.-(N-methyl-N-2-adamantylcarbamoyl)-4-aza-4-methyl-androstan-3-one;
17.beta.-(N-2-adamantylcarbamoyl)-4-methyl-4-aza-5.alpha.-androstan-3-one;
and
17.beta.-(N-methyl-N-2-adamantyl)carbamoyl-4-methyl-4-aza-androst-1-en-3-on
e.
The corresponding compounds of those above wherein the 4-aza
substituent is substituted in each of the above named compounds
with a hydrogen, methyl or an ethyl radical, to form a different
N-substituent, and wherein a double bond can be optionally present
as indicated by the dotted line in position 1.
The alkyl, cycloalkyl, aralkyl, monocyclic aryl, 1-, 2-adamantyl or
1-, 2-norbornanyl moieties can be substituted with one or more
substituents of the following: C.sub.1 -C.sub.4 linear/branched
alkyl, including methyl, ethyl, isopropyl, n-butyl; nitro; oxo;
C.sub.7 -C.sub.9 aralkyl, including benzyl; (CH.sub.2)n COOR where
n is 0-2 and R is H or C.sub.1 -C.sub.4 linear/branched alkyl
including methyl, ethyl; CH.sub.2 OH; OH; OR where R is C.sub.1
-C.sub.4 linear/branched alkyl including methyl, ethyl; halo,
including fluoro, bromo, iodo; COOH; COOR, where R is
linear/branched C.sub.1 -C.sub.4 alkyl; --CONH.sub.2 ; CH.sub.2
NH.sub.2 ; CH.sub.2 NHCOR where R is C.sub.1 -C.sub.4
linear/branched alkyl including methyl, ethyl; phenyl; o, m,
p-substituted phenyl including p-nitro, p-amino and p-sulfo; or
cyano. The amino group of the adamantyl or norbornanyl moiety can
also be substituted as R.sup.1 with methyl and ethyl, as well as
hydrogen.
Also included within the scope of this invention are
pharmaceutically acceptable salts or esters, where a basic or
acidic group is present on the substituted alkyl, cycloalkyl,
aralkyl, adamantyl or norbornanyl moiety. When an acidic
substituent is present, i.e. --COOH, there can be formed the
ammonium, sodium, potassium, calcium salt, and the like, for use as
the dosage form.
Where a basic group is present, i.e. amino, acidic salts, i.e.
hydrochloride, hydrobromide, acetate, pamoate, and the like, can be
used as the dosage form.
Also, in the case of the --COOH group being present,
pharmaceutically acceptable esters can be employed, e.g. acetate,
maleate, pivaloyloxymethyl, and the like, and those esters known in
the art for modifying solubility or hydrolysis characteristics for
use as sustained release or prodrug formulations.
Representative examples include for R.sup.2 (where AD is
adamantyl):
3,5,7-trinitro-1-AD; 4-oxo-1-AD; 1-benzyl-1-AD; 4,4-dimethyl-1-Ad;
3,7-dimethyl-5-carboxymethyl-1-AD; 3-carboxymethyl-1-AD;
3-chloro-1-AD; 1,3-dihydroxy-6,6-dimethyl-2-AD; 3-chloro-1-AD;
4-carbethoxy-2-AD; 4-carboxy-2-AD; 3-isopropyl-1-AD;
3-n-butyl-1-AD; 3-propyl-1-AD; 3-,5-diethyl-1-AD;
3-hydroxymethyl-1-AD; 2-carboxy-1-AD; 3-methyl-1-AD;
5-hydroxy-2-AD; 2-hydroxy-1-AD; 1-aminomethyl-1-hydroxy-2-AD;
2-oxo-1-AD; 2-phenyl-2-AD; 1-amino-methyl-2-AD; 1-carboxy-2-AD;
1-aminocarbonyl-2-AD; 3-hydroxy-5,7-dimethyl-1-AD; 4-fluoro-1-AD;
3-fluoro-1-AD; 4-hydroxy-2-AD; 3-phenyl-1-AD;
3-(p-aminophenyl)-1-AD; 3-(p-nitrophenyl)-1-AD;
3-methyl-5-hydroxymethyl-1-AD; 3,5-dimethyl-4-hydroxy-1-AD;
2-hydroxymethyl-2-AD; 3-(p-sulfophenyl)-1-AD;
3-methyl-5-ethyl-1-AD; 2-carboxy-2-AD; 3,5-7-trimethyl-1-AD;
4-iodo-2-AD; 4-bromo-2-AD; 4-chloro-2-AD; 1-acetylaminomethyl-2-AD;
1-carboxymethyl-2-AD; 1-methyl-2-AD; 1-aminocarboxylmethyl-2-AD;
1-aminocarboxyl-1-AD; 2-cyano-2-AD; 3,5-dimethyl-7-ethyl-1-AD;
4-hydroxy-1-AD; 1-hydroxy-2-AD; 5-carboxy-3-methyl-1-AD;
3,5-dimethyl-7-carboxy-1-AD; 3-carboxy-1-AD; 3-hydroxy-1-AD; and
the like.
Representative examples include for R.sup.2 as substituted
norbornanyl moieties are (where NB is norbornanyl):
2-NB; 1,7,7-trimethyl-4-phenyl-2-NB; 3-carboxy-2-NB;
3-phenyl-2-carboxy-2-NB; 2-cyano-3-phenyl-2-NB;
3-hydroxy-4,7,7-trimethyl-2-NB; 6-hydroxymethyl-2-NB; 5-cyano-2-NB;
3-allyl-2-NB; 1-NB; 7,7-dimethyl-1-hydroxymethyl-2-NB;
3-methoxy-4,7,7-trimethyl-2-NB; 3-aminocarbonyl-2-NB;
3-ethoxycarbonyl-2-NB; 3,3-dimethyl-2-NB; 7-oxo-1-NB;
3-phenyl-2-NB; 1-carboxy-methyl-7,7-dimethyl-2-NB; 1-ethyl-2-NB;
1-methyl-2-NB; 2,2,3,3,5,5,6,6,7,7-decafluoro-1-NB; 3-hydroxy-2-NB;
3-chloro-2-NB; 3-(p-methoxyphenyl)-2-NB;
2,2-dimethyl-3-methylene-7-NB; 3-oxo-2-NB; 1-methoxy-2-NB; 7-NB;
3-isopropyl-2-NB; 2-bromo-1-NB; 3-chloro-1-NB; and the like.
Procedures for preparing the compounds of Formula I useful in this
invention, including the above, are well known in the art.
The novel compounds of formula I of the present invention can be
prepared by a method starting with the known steroid ester (III) of
the formula: ##STR3##
17.beta.-(carbomethoxy)-4-aza-5-.alpha.-androstan-3-ones which
includes the stages of optionally 1) dehydrogenating said starting
material to produce the corresponding compound containing a
double-bond in the 1,2-position of the A-ring, 2) converting the
17-carbomethoxy substituent into an N-substituted alkyl,
cycloalkyl, aralkyl, monocylic acyl, or adamantylcarbamoyl
substituent and, if desired, 3) alkylating the A-ring nitrogen to
introduce a N-methyl or N-ethyl substituent into the A ring
4-position. For the dehydrogenatin step, it is preferable that the
4-aza nitrogen be unsubstituted. The alternate pathways can consist
of one or more discrete chemical steps and if desired can take
place before step (1) or following step (1) or step (3).
In accordance with the process of the present invention (see flow
sheet), the products of our invention are formed by optionally: (1)
heating a 17.beta.-alkoxycarbonyl-4-aza-5.alpha.-androstan-3-ones,
compound III, (prepared in the literature as described in the
reference U.S. Pat. No. 4,377,584) with a dehydrogenating agent
such as benzeneseleninic anhydride in a refluxing inert solvent,
e.g. chlorobenzene, to form a
17.beta.-alkoxycarbonyl-4-aza-5.alpha.-androst-1-ene-3-one IV
(alternately, the dichlorodicyanobenzoquinone process of Dolling,
et al., JACS 1988, Vol. 110, pp. 3318-3319, can be used); (2) the
formed 5.alpha.-androst-1-en-3-one compound from Step 1 can be
reacted with, e.g. sodium hydride under anhydrous conditions in a
neutral solvent such as dimethylformamide; (3) contacting the
resulting reaction mixture with an alkyl (methyl or ethyl) iodide
to form the corresponding
17-.beta.-alkoxy-adamantyl-carbamoyl-4-alkyl-4-aza-5.alpha.-androst-1-en-3
-one V; (4) subsequently hydrolyzing said
17.beta.-alkoxycarbonyl-4-alkyl-4-aza-5.alpha.-androst-1-en-3-one
with a strong base, such as aqueous methanolic potassium hydroxide
at the reflux temperature, followed by acidification and isolation
of the resulting steroidal acid to yield 17.beta.-carboxy
4-alkyl-4-aza-5.alpha.-androst-1-en-3-one VI; (5) said steroidal
acid can be then converted to its corresponding 2-pyridylthio ester
by refluxing with triphenyl phosphine and 2,2'-dipyridyl disulfide
in an inert solvent such as toluene and the resulting product
17.beta.-(2-pyridylthiocarbonyl)-4-alkyl-4-aza-5.alpha.-androst-1-en-3-one
VII can be isolated by chromatography on e.g. silica gel; and (6)
said pyridylthio ester can be thenreacted with 1-adamantyl-,
2-adamantylamine or norbornanylamine in an inert solvent e.g.
tetrahydrofuran, to form the desired product
17.beta.-N-adamantylcarbamoyl-4-alkyl-4-aza-5.alpha.-androst-1-en-3-one
VIII which can be isolated by chromatography e.g. on silica gel.
When the previous reaction is carried out in the absence of first
forming the double bond at position 1, the corresponding
17.beta.-(N-adamantylcarbamoyl)-4-alkyl-4-aza-5.alpha.-androstan-3-one
(or N-norbornanyl carbamoyl compound) is prepared.
In accordance with an alternate process of our invention the
corresponding
N-unsubstituted-17.beta.(N-adamantyl-carbamoyl)-4-aza-5.alpha.-androst-1-e
n-3-one XIV is readily prepared from the 17.beta.
(alkoxycarbonyl)-4-aza-5.alpha.-androstone-3-one IV by repeating
the above series of reaction steps but omitting the alkylation Step
2 herein above, i.e. treatment of the
4-aza-5-.alpha.-androst-1-en-3-one with e.g. sodium amide followed
by methyl or ethyl iodide via intermediates XII and XIII.
In accordance with a further alternate process of preparing the
compounds of our invention having only hydrogen as the sole
substituent on the ring A--nitrogen, the double bond in the A ring
is introduced as the last step of the process. Thus, a
17.beta.-alkoxycarbonyl 4-aza-5.alpha.-androstan-3-one III is
hydrolyzed to the corresponding steroidal acid IX
17.beta.-carboxy-4-aza-5.alpha.-androstan-3-one which in turn is
converted to the corresponding pyridylthio ester, 17.beta.
(2-pyridylthiocarbonyl)-4-aza-5.alpha.-androstan-3-one, X followed
by treatment of the ester with an amine of formula R.sup.2
-NH.sub.2 wherein R.sup.2 is as defined hereinabove as 1- or
2-adamantyl or 1-, 2-, or 7-norbornanyl to form a 17.beta.
(N-adamantyl-carbamoyl)-4-aza-5.alpha.-androstone-3-one XI which is
dehydrogenated as previously described to produce compound XIV,
17.beta.-(N-adamantyl-carbamoyl)-4-aza-androst-1-en-3-one or
corresponding norbornanyl derivative.
In another alternate method of introducing the
17.beta.-(N-adamantyl-carbamoyl)substituent into a 17.beta.-carboxy
androstane compound of formula VI, XII or IX, each is treated in a
manner similar to the procedure described in Steroids, Vol. 35 #3,
March 1980, p. 1-7 with dicyclohexylcarbodiimide and
1-hydroxybenzo-triazole to form the
17.beta.-(1-benzotriazoloxycarbonyl)-4-aza-5.alpha.-androst-1-en-3-one,
VII, XIII or compound X, wherein the substituent X is
benzotriazoloxy group.
The 16-methyl derivative wherein R'" is methyl are prepared from
known 16-methyl-17-acyl-4-methyl-4-aza-5.alpha.-androstan-3-ones,
e.g.
4,16.beta.-dimethyl-17.beta.-acetyl-4-aza-5.alpha.-androstan-3-one
by known dehydrogenation procedures for 4-methyl-4-aza compounds to
produce the corresponding
4,16.beta.-dimethyl-17.beta.-acetyl-4-aza-5.alpha.-androst-1-en-3-one.
The above reactions are schematically represented in the following
flowsheet. ##STR4##
X is 2-pyridylthio or 1-benzotriazoloxy.
R.sup.2 is 1- or 2-adamantyl or norbornanyl.
Also a preferred 4-azasteroid is a
17.beta.-acyl-4-aza-5.alpha.-androst-1-ene-3-one compound of the
formula: ##STR5## wherein the dotted line represents a double bond
when present; R is selected from hydrogen, methyl and ethyl;
R.sup.2 is (a) a monovalent radical selected from straight or
branched chain alkyl, or cycloalkyl, of from 1-12 carbons, which
can be substituted by one or more of C.sub.1 -C.sub.2 alkyl or
halo;
(b) an aralkyl radical selected from benzyl or phenethyl;
(c) a polycyclic aromatic radical which can be substituted with one
or more of: --OH, protected --OH, --OC.sub.1 -C.sub.4 alkyl,
C.sub.1 -C.sub.4 alkyl, halo or nitro;
(d) a monocyclic aromatic radical which can be substituted with one
or more of:
(1) --OH, --OC.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkyl,
--(CH.sub.2).sub.m OH, --(CH.sub.2).sub.n, COOH, including
protected hydroxy, where m is 1-4, n is 1-3, providing C.sub.1
-C.sub.4 alkyl is only present when one of the above
oxygen-containing radicals is present;
(2) --SH, --SC.sub.1 -C.sub.4 alkyl, --SOC.sub.1 -C.sub.4 alkyl,
--SO.sub.2 C.sub.1 -C.sub.4 alkyl, --SO.sub.2 N(C.sub.1 -C.sub.4
-alkyl).sub.2, C.sub.1 -C.sub.4 alkyl --(CH.sub.2).sub.m SH,
--S--(CH.sub.2).sub.n --O-- COCH.sub.3, where m is 1-4 n is 1-3,
providing C.sub.1 -C.sub.4 alkyl is only present when one of the
above sulfur containing radicals is present;
(3) N(R.sup.3).sub.2, which can be protected, where R.sup.3 is
independently H or C.sub.1 -C.sub.4 alkyl, where the monoaryl ring
can also be further substituted with C.sub.1 -C.sub.4 alkyl;
and
(4) heterocyclic radical selected from 2- or 4-pyridyl, 2-pyrrolyl,
2-furyl or thiophenyl;
and R', R" and R'" are each selected from hydrogen and methyl, and
pharmaceutically acceptable salts thereof.
A preferred embodiment of the compounds of our invention process
is:
the compound of above Structure IA,
wherein the dotted line is a double bond,
R is hydrogen or methyl, and
R.sup.2 is branched chain alkyl, or cycloalkyl of from 4-10
carbons, and R" and R'" are hydrogen.
Another embodiment of the invention is the compounds of above
Structure I where R.sup.2 is phenyl, or phenyl substituted by
substituents described above, including where
R.sup.2 is phenyl, 2-, 3-, or 4-tolyl, xylyl, 2-bromophenyl,
2-chlorophenyl, 2,6-dichlorophenyl, 2,6-dibromophenyl, aminophenyl,
N-alkylaminophenyl, N-N-dialkylaminophenyl, 4-biphenyl, 3-biphenyl,
naphthyl, anthracyl, phenanthryl, thiophenyl, methylthiophenyl,
methylsulfinyl, phenyl, methylsulfophenyl, aminosulfophenyl,
thioethylphenyl, acetoxymethylthiophenyl,
17.beta.-(4-hydroxyphenyl), 17.beta.-(3-hydroxyphenyl),
17.beta.-(3,4-dihydroxyphenyl), or
17.beta.-(3,5-dimethyl-4-hydroxyphenyl).
Representative compounds of the invention are:
17.beta.-(phenylcarbonyl)-4-aza-4-methyl-5.alpha.-androst-1-ene-3-one;
17.beta.-(2-tolylcarbonyl)-4-aza-4-methyl-5.alpha.-androst-1-ene-3-one;
17.beta.-(3-tolylcarbonyl)-4-aza-4-methyl-5.alpha.-androst-1-ene-3-one;
17.beta.-(4-tolylcarbonyl)-4-aza-4-methyl-5.alpha.-androst-1-ene-3-one;
17.beta.-(2-bromophenylcarbonyl)-4-aza-4-methyl-5.alpha.-androst-1-ene-3-on
e;
17.beta.-(2-chlorophenylcarbonyl)-4-aza-4-methyl-5.alpha.-androst-1-ene-3-o
ne;
17.beta.-(2,6-dichlorophenylcarbonyl)-4-aza-4-methyl-5.alpha.-androst-1-ene
-3-one;
17.beta.-(2,6-dibromophenylcarbonyl)-4-aza-4-methyl-5.alpha.-androst-1-ene-
3-one;
17.beta.-(xylylcarbonyl)-4-aza-4-methyl-5.alpha.-androst-1-ene-3-one;
17.beta.-(t-butylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(isobutylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(isooctylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(n-octylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(1,1-diethylbutylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(neopentylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(tert-amylcarbonyl)-4-aza-4-5.alpha.-androst-1-ene-3-one;
17.beta.-(tert-hexylcarbonyl)-4-aza-4-5.alpha.-androst-1-ene-3-one;
17.beta.-(cyclohexylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(cyclopentylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(benzylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(2-pyridylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(4-pyridylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(2-pyrrolylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(2-furylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(2-thiophenylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(2-adamantylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(3-(phenylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(2-tolylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(3-tolylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(4-tolylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(2-bromophenylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(2-chlorophenylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(2,6-dichlorophenylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(2,6-dibromophenylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(xylylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(phenylethyl)carbonyl-4-aza-5.alpha.-androst-1-ene-3-one;
17.beta.-(4-dimethylaminophenylcarbonyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(3-dimethylaminophenylcarbonyl)-4-aza-5.alpha.-androst-1-en-3-one.
17.beta.-(3,4-diethylaminophenylcarbonyl)-4-aza-androst-1-en-3-one.
17.beta.-(3,5-dimethyl-4-diethylaminophenylcarbonyl)-4-aza-5.alpha.-androst
-1-en-3-one;
17.beta.-(4-N-methylaminomethylphenylcarbonyl)-4-aza-5.alpha.-androst-1-en-
3-one; or
17.beta.-(2-N-ethylamino-4-ethylphenylcarbonyl)-4-aza-5.alpha.-androst-1-en
-3-one.
17.beta.-(4-phenylbenzoyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(3-phenylbenzoyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(4-biphenyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(3-biphenyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(1-naphthyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(2-naphthyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(1-phenanthryl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(2-phenanthryl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(1-biphenyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(9-anthracyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(4-thiophenylcarbonyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(3-thiophenylcarbonyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(4-methylthiophenylcarbonyl
)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(4-methylsulfinylphenylcarbonyl)-4-aza-5.alpha.-androst-1-en-3-one
;
17.beta.-(4-methylsulfophenylcarbonyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(3-methylsulfinylphenylcarbonyl)-4-aza-5.alpha.-androst-1-en-3-one
;
17.beta.-(4-N,N-dimethylaminosulfophenylcarbonyl)-4-aza-5.alpha.-androst-1-
en-3-one;
17.beta.-(2-ethyl-4-methylthiophenylcarbonyl)-4-aza-5.alpha.-androst-1-en-3
-one;
17.beta.-(4-thioethylphenylcarbonyl)-4-aza-4-methyl-5.alpha.-androst-1-en-3
-one;
17.beta.-(4-acetoxymethylthiophenylcarbonyl)-4-aza-4-methyl5.alpha.-androst
-1-en-3-one;
17.beta.-(2-methyl-4-methylthiophenylcarbonyl)-4-aza-4-methyl-5.alpha.-andr
ost-1-en-3-one;
17.beta.-(2-methyl-4-methylsulfinylphenylcarbonyl)-4-aza-4-methyl-5.alpha.-
androst-1-en-3-one;
17.beta.-(2-isopropyl-4-methylsulfophenylcarbonyl)-4-aza-4-methyl-5.alpha.-
androst-1-en-3-one;
17.beta.-(4-methylthiophenylcarbonyl)-4-aza-4-methyl-5.alpha.-androstan-3-o
ne;
17.beta.-(4-methylsulfinylphenylcarbonyl)-4-aza-4-methyl-5.alpha.-androstan
-3-one;
17.beta.-(4-methylsulfophenylcatbonyl)-4-aza-4-methyl-5.alpha.-androstan-3-
one;
17.beta.-(4-hydroxyphenyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(3-hydroxyphenyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(3,4-dihydroxyphenyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(3,5-dimethyl-4-hydroxyphenyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(4-hydroxymethylphenyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(2-hydroxyethylphenylcarbonyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(4-methoxyphenyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(4-carboxymethylphenyl)-4-aza-5.alpha.-androst-1-en-3-one;
17.beta.-(4-hydroxyphenyl)-4-aza-4-methyl-5.alpha.-androst-1-en-3-one;
17.beta.-(3-hydroxyphenyl)-4-aza-4-methyl-5.alpha.-androst-1-en-3-one;
17.beta.-(3,4-dihydroxyphenyl)-4-aza-4-methyl-5.alpha.-androst-1-en-3-one;
17.beta.-(3,5-dimethyl-4-hydroxyphenyl)-4-aza-4-methyl-5.alpha.-androst-1-e
n-3-one;
17.beta.-(4-hydroxymethylphenyl)-4-aza-4-methyl-5.alpha.-androst-1-en-3-one
;
17.beta.-(2-hydroxyethylphenylcarbonyl)-4-aza-4-methyl-5.alpha.-androst-1-e
n-3-one;
17.beta.-(4-methoxyphenyl)-4-aza-4-methyl-5.alpha.-androst-1-en-3-one;
17.beta.-(4-carboxymethylphenyl)-4-aza-4-methyl-5.alpha.-androst-1-en-3-one
; and
17.beta.-(4-carboxyphenyl)-4-aza-5.alpha.-androst-1-en-3-one, and
the corresponding compounds wherein the 4-hydrogen substituent is
replaced in each of the above named compounds by a methyl or an
ethyl radical.
The compounds of formula IA of the present invention are prepared
by a method starting with the known steroid ester of the formula:
##STR6## named
17.beta.-(carbomethoxy)-4-aza-5.alpha.-androstan-3-one, which
includes the stages of (1) dehydrogenating said starting material
to produce the corresponding compound containing a double bond in
the 1,2-position of the A-ring, (2) converting the 17-carbomethoxy
substituent into a 17.beta.-acyl substituent and, if desired (3)
alkylating the A-ring nitrogen to introduce 4-methyl or 4-ethyl
substituents into the A-ring. For the dehydeogenation step, it is
preferable that the 4-aza nitrogen be unsubstituted, The
dehydrogenation step can be carried out, e.g. according to the
procedure of Dolling, et al. involving dichlorodicyanobenzoquinone,
JACS (1988) Vol. 110, pp. 3318-3319. Stage (2) may consist of one
or more chemical steps and if desired may take place before stage
(1) or following stage (1) or stage (3).
In accordance with the process of the present invention, the
products of our invention are formed by (1) heating a
17.beta.-alkoxycarbonyl-4-aza-5.alpha.-androstan-3-one compound III
with a dehydrogenating agent such as benzeneseleninic anhydride in
refluxing chlorobenzene to form a
17.beta.-alkoxycarbonyl-4-aza-5.alpha.-androst-1-en-3-one (IV), (2)
the formed 5.alpha.-androst-1-en-3-one compound from step (1) is
reacted with sodium hydride and under anhydrous conditions in a
neutral solvent such as dimethylformamide, (2) contacting the
resulting reaction mixture with an alkyl (methyl or ethyl) iodide
to form the corresponding
17.beta.-alkoxycarbonyl-4-alkyl-4-aza-5.alpha.-androst-1-en-3-one
(V), (3) subsequently hydrolyzing said
17.beta.-alkoxycarbonyl-4-alkyl-4-aza-5.alpha.-androst-1-en-3-one
with a strong base such as aqueous methanolic potassium hydroxide
at the reflux temperature, followed by acidification and isolation
of the resulting steroidal acid,
17.beta.-carboxy-4-alkyl-4-aza-5.alpha.-androst-1-en-3-one (VI),
(4) said steroidal acid is then converted to its corresponding
2-thiopyridyl ester by refluxing with triphenyl phosphine and
2,2'-dipyridyl disulfide in an inert solvent and the product
17.beta.-(2-pyridylthiocarbonyl)-4-alkyl-4-aza-5.alpha.-androst-1-en-3-one
(VII) is isolated by chromatography on silica, (5) said pyridylthio
ester is then reacted with an R.sup.2 -Li or an R.sup.2 MgX (X=Cl,
Br) compound, such as sec-butylmagnesium chloride in
tetrahydrofuran, to form the desired product, e.g.,
17.beta.-(sec-butylcarbonyl)-4-alkyl-4-aza-5.alpha.-androst-1-en-3-one
(VIII) which is isolated by chromatography on silica gel. When the
previous reaction is carried out using an R.sup.2 MgX or, an
R.sup.2 -Li compound in place of sec-butylmagnesium chloride, the
corresponding
17.beta.-(acyl)-4-alkyl-4-aza-5.alpha.-androst-1-en-3-one is
prepared wherein acyl is R.sup.2 carbonyl.
In accordance with the process of our invention, the corresponding
17.beta.-acyl-4-aza-5.alpha.-androst-1-en-3-one XV is readily
prepared from the
17.beta.(alkoxycarbonyl)-4-aza-5.alpha.-androsten-3-one (IV) by
repeating the above series of reaction steps but omitting step 2
hereinabove, i.e., treatment of the
4-aza-5.alpha.-androst-1-en-3-one with sodium amide followed by
methyl or ethyl iodide.
In accordance with a further alternate process of preparing the
compounds of our invention, having only hydrogen as the sole
substituent on the ring A-nitrogen, the 1,2-double bond in the
A-ring is introduced as the last step of the process. Thus, a
17.beta.-alkoxycarbonyl-4-aza-5.alpha.-androstan-3-one (III) is
hydrolyzed to the corresponding steroidal acid,
17.beta.-carboxy-4-aza-5.alpha.-androstan-3-one, (IX) which, in
turn, is converted to the corresponding thiopyridyl ester,
17.beta.-(2-pyridylthiocarbonyl)-4-aza-5.alpha.-androstan-1-one (X)
followed by treatment of the ester with an R.sup.2 MgX or R.sup.2
Li compound wherein R.sup.2 is as defined hereinabove to form a
17.beta.-(acyl)-4-aza-5.alpha.-androstan-3-one (XI) which is
dehydrogenated as previously described to produce compound XIV,
17.beta.-(acyl)-4-aza-5.alpha.-androst-1-en-3-one.
In an additional alternative process for making the compounds of
formula I when the starting material is an ester, particularly
methyl ester as shown in formula III-V in the schematic, reaction
with a Grignard reagent R.sup.2 MgX, gives the ketone,
17.beta.-R.sup.2 CO--, corresponding to the R.sup.2 moiety
associated with the Grignard reagent.
The 16-methyl derivative wherein R'" is methyl are prepared from
known
16-methyl-17.beta.-acyl-4-methyl-4-aza-5.alpha.-androstan-3-ones,
e.g.
4,16.beta.-dimethyl-17.beta.-acetyl-4-aza-5.beta.-androstan-3-one
by known dehydrogenation procedures for 4-methyl-4-aza compounds to
produce the corresponding
4,16.beta.-dimethyl-17.beta.-acetyl-4-aza-5.alpha.-androst-1-en-3-one.
The above reactions are schematically represented in the following
structural outline: ##STR7## wherein X is a 2-pyridylthio
substituent and R.sup.2 is defined as hereinabove.
In the above described reaction Scheme, where R.sup.2 is
p-hydroxybiphenyl, this can be derived by starting with an
appropriate bromobiphenylylphenol, e.g. p-bromobiphenylphenol,
protecting the phenolic --OH with a conventional blocking group,
e.g. trioganosilyl, i.e. t-butyldimethylsilyl, carrying out the
Grignard reaction and then deblocking the silyl group by the use
of, e.g. refluxing aqueous tetrabutylammonium fluoride.
Other halo substituted benzenes to form the appropriate Grignard
reagent useful in the instant invention will be obvious to one
skilled in the art from this disclosure.
By the term "protected hydroxy" as used herein, is meant the
alcoholic or carboxylic --OH groups which can be protected by
conventional blocking groups in the art as described in "Protective
Groups In Organic Synthesis" by Theodora W. Greene,
Wiley-Interscience, 1981, New York. Preferred are the
triorganosilyl groups, e.g. t-butyldimethylsilyl,
phenyldimethylsilyl, diphenylmethylsilyl, and the like.
By the term "C.sub.1 -C.sub.4 alkyl" is used herein, is meant
linear or branched alkyl, including methyl, ethyl, propyl,
isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.
When this reaction scheme is carried out using an R.sup.2 MgX or
R.sup.2 -Li compound containing an thiophenyl substituted R.sup.2,
e.g. p-methylthiophenyl magnesium chloride, the corresponding
17.beta.-(substituted thio-benzoyl)-4-alkyl
aza-5.alpha.-androst-1-en-3-one is prepared wherein phenyl is
R.sup.2.
The Grignard reagent, R.sup.2 MgX, for all the species included
within the scope of this invention, are available or can readily be
made by one skilled in the art. For example, where R.sup.2 is
C.sub.1 -C.sub.4 alkyl thiophenyl, can be formed from the
appropriate C.sub.1 -C.sub.4 alkyl thiobromobenzene, e.g.
p-methylthiobromobenzene.
The formed C.sub.1 -C.sub.4 alkyl thiobenzene can be used to
further prepare C.sub.1 -C.sub.4 alkyl sulfoxides by oxidation with
e.g. m-chloroperbenzoic acid. The resulting sulfoxide can be
further oxidized by the use of the m-chloroperbenzoic acid reaction
to proceed for a longer period of time to form the C.sub.1 -C.sub.4
alkyl sulfone.
Further, the sulfoxide can be used in the Pummerer rearrangement to
form the corresponding thiol.
The --SO.sub.2 N(C.sub.1 -C.sub.4 alkyl).sub.2 substituted phenyl
(R.sup.2) is formed from the appropriate bromobenzene, e.g.
p-N,N-dimethylaminosulfobromobenzene which is used directly in the
Grignard reaction to form the final product.
The thioalkyl groups on the phenyl ring, i.e. --(CH.sub.2).sub.m
SH, where m is 1-4, are readily formed via a four step procedure
from an alkoxy alkyl phenyl bromide, Br--C.sub.6 H.sub.4
--(CH.sub.2).sub.m OCH.sub.3. Direct addition of the Grignard
reagent prepared from above-bromoalkyl phenyl derivative to the
thiopyridyl ester results in the keto derivative, i.e.
17.beta.(4-methoxyalkyl-benzoyl)-4-aza-5.alpha.-androst-1-ene-3-one.
This can be readily converted into thio analogue via BBr.sub.3 at
-70.degree. C. to form the hydroxyalkyl derivative, followed by
displacement by halogen, e.g. bromo and then converting the
halogenated compound through NaSH displacement to give the final
mercapto compound. Where in the Reaction Scheme said pyridylthio
ester is reacted with an aminophenyl containing R.sup.2 -Li or an
R.sup.2 MgX (X=Cl, Br) compound, such as p-dimethylaminophenyl
magnesium chloride, this is carried out in tetrahydrofuran to form
the desired product
17.beta.-(p-dimethylaminophenyl-carbonyl)-4-alkyl-4-aza-5.alpha.-androst-1
-en-3-one (VIII) which is isolated by chromatography on silica
gel.
The Grignard reagent, R.sup.2 MgX, for all of the aminophenyl
species included within the scope of this invention, are available
and can be made readily by one skilled in the art.
Where in the process said Grignard reagent contains a phenolic type
R.sup.2 moiety, then said pyridylthio ester is then reacted with an
R.sup.2 -Li or an R.sup.2 MgX (X=Cl, Br) Grignard reagent, such as
p-methoxyphenyl-magnesium chloride in tetrahydrofuran to form the
desired product, e.g.
17.beta.-(p-methoxyphenylcarbonyl)-4-alkyl-4-aza-5.alpha.-androst-1-en-3-o
ne (VIII) which is isolated by chromatography on silica gel. When
this reaction is carried out using another R.sup.2 MgX or, an
R.sup.2 -Li compound in place of p-methoxyphenylmagnesium chloride,
the corresponding 17.beta.-(substituted
benzoyl)-4-alkyl-4-aza-5.alpha.-androst-1-en-3-one is prepared
wherein phenyl is R.sup.2.
The Grignard reagent, R.sup.2 MgX, for all of the species included
within the scope of this invention, are available and can be made
readily by one skilled in the art.
For example, where R.sup.2 is hydroxyphenyl, this can be derived by
starting with an appropriate bromophenol, e.g. p-bromophenol,
protecting the phenolic --OH with a conventional blocking group,
e.g. trioganosilyl, i.e. t-butyldimethylsilyl, carrying out the
Grignard reaction and then deblocking the silyl group by the use
of, e.g. refluxing aqueous tetrabutylammonium fluoride.
For R.sup.2 being hydroxyethylphenyl, the same blocking procedure
can be analogously conducted starting with the appropriate
hydroxyalkyl bromophenol, e.g. p-hydroxymethylbromobenzene, or
p-hydroxyethylbromobenzene.
Where R.sup.2 is carboxyphenyl, this can be obtained by the chromic
acid oxidation of the appropriate hydroxymethylbenzene, e.g.
p-bromo-hydroxymethylbenzene, formed as described above.
Where R.sup.2 is -O-C.sub.1 -C.sub.4 alkyl, the appropriate
bromo-O-C.sub.1 -C.sub.4 alkyl benzene, e.g. p-methoxybromobenzene,
is utilized for the Grignard reaction.
Other halo substituted benzenes to form the appropriate Grignard
reagent useful in the instant invention will be obvious to one
skilled in the art from this disclosure.
By the term "protected hydroxy" as used herein, is meant the
alcoholic or carboxylic --OH groups which can be protected by
conventional blocking groups in the art as described in "Protective
Groups In Organic Synthesis" by Theodora W. Greene,
Wiley-Interscience, 1981, New York. Preferred are the
triorganosilyl groups, e.g. t-butyldimethylsilyl,
phenyldimethylsilyl, diphenylmethylsilyl, and the like.
Also within the scope of the present invention is the use of ketone
reduction products of IA, in combination with flutamide for
treatment of prostatic carcinoma, being secondary alcohols of the
formula: ##STR8## wherein R is selected from hydrogen, methyl and
ethyl; R.sup.2 is (a) a monovalent radical selected from straight
or branched chain alkyl, or cycloalkyl, of from 1-12 carbons, which
can be substituted by one or more of C.sub.1 -C.sub.2 alkyl or
halo;
(b) an aralkyl radical selected from benzyl or phenethyl;
(c) a polycyclic aromatic radical which can be substituted with one
or more of: --OH, protected --OH, --OC.sub.1 -C.sub.4 alkyl,
C.sub.1 -C.sub.4 alkyl, halo or nitro;
(d) a monocyclic aromatic radical which can be substituted with one
or more of:
(1) --OH, --OC.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkyl,
--(CH.sub.2).sub.m OH, --(CH.sub.2).sub.n COOH, including
protecting hydroxy, where m is 1-4, n is 1-3, providing C.sub.1
-C.sub.4 alkyl is only present when one of the above
oxygen-containing radicals is present;
(2) --SH, --SC.sub.1 -C.sub.4 alkyl, --SOC.sub.1 -C.sub.4 alkyl,
--SO.sub.2 C.sub.1 -C.sub.4 alkyl, --SO.sub.2 N(C.sub.1 -C.sub.4
-alkyl).sub.2, C.sub.1 -C.sub.4 alkyl --(CH.sub.2).sub.m SH,
--S--(CH.sub.2).sub.n --O-- COCH.sub.3, where m is 1-4 n is 1-3,
providing C.sub.1 -C.sub.4 alkyl is only present when one of the
above sulfur containing radicals is present;
(3) N(R.sup.3).sub.2, which can be protected, where R.sup.3 is
independently H or C.sub.1 -C.sub.4 alkyl, where the monoaryl ring
can also be further substituted with C.sub.1 -C.sub.4 alkyl;
and
(4) heterocyclic radical selected from 2- or 4-pyridyl, 2-pyrrolyl,
2-furyl or thiophenyl;
R', R" and R'" are hydrogen or methyl, wherein the dotted line
represents a double bond which can be present, and pharmaceutically
acceptable salts and esters thereof.
These compounds can be made by conventional sodium borohydride
reduction of the carbonyl attached to R.sup.2 without reducing the
amide carbonyl in Ring A or the 1,2-double bond, if present. If the
R.sup.2 phenyl contains a carbonyl function, it can be selectively
blocked and then regenerated after the borohydride reduction by
conventional methods.
The borohydride reduction can be carried out in, e.g. water or
aqueous methanol, at a temperature of room temperature to
50.degree. C. and the product then isolated and purified by
conventional means. The compounds are also active as 5-alpha
reductase inhibitors in the treatment of patterned alopecia.
The compounds of the present invention, prepared in accordance with
the method described above, are, as already described, potent
agents in combination with an antiandrogen, e.g. flutamide for the
treatment of prostatic cancer.
17.beta.-substituted steroidal 5.alpha.-reductase inhibitors which
are non-4-aza steroids are known in the art and include those
developed by SmithKline Beckmann as disclosed in U.S. Pat. No.
4,882,319 to Holt, et al.; U.S. Pat. No. 4,910,226 to Holt, et al;
EPO Publn. 0 289 327 now U.S. Pat. No. 4,910,226; EPO Publn. 0 277
002 now U.S. Pat. No. 4,888,336; EPO Publn. 0 343 954; EPO Publn. 0
375 344 now U.S. Pat. No. 4,937,237; EPO Publn. 0 375 347; now U.S.
Pat. No. 4,970,205; EPO Publn. 0 375 349; now U.S. Pat. No.
5,026,882.
In the method the 17.beta.-substituted non-aza steroids are of the
formula: ##STR9## in which: the A ring has up to 2 double
bonds;
the B, C, and D rings have optimal double bonds where indicated by
the broken lines, provided that the A, B, and C rings do not have
adjacent double bonds and the D ring does not have a C.sub.16
-C.sub.17 double bond when R.sub.3 represents two substituents or a
divalent substituent;
Z is (CH.sub.2)n and n is 0 or 2, provided that Z is (CH)n when
adjacent to a double bond;
X is H, Cl, F, Br, I, CF.sub.3, or C.sub.1-6 alkyl;
Y is H, CF.sub.3, F, Cl, or CH.sub.3, provided that Y is H when
there is no C.sub.5 -C.sub.6 double bond;
R.sup.1 is H or C.sub.1-8 alkyl;
R.sup.2 is absent or present as H or CH.sub.3, provided R.sup.2 is
absent when the carbon to which it is attached is unsaturated;
and
R.sup.3 is
(1) .alpha.-hydrogen, or .alpha.-hydroxyl, or .alpha.-acetoxy
and/or
(a) ##STR10## where W is a bond or C.sub.1-12 alkylidene, and
R.sup.4 is (i) hydrogen,
(ii) hydroxyl,
(iii) C.sub.1-8 alkyl,
(iv) hydroxylic C.sub.1-8 alkyl,
(v) C.sub.1-8 alkoxy,
(vi) NR.sup.5 R.sup.6, where R.sup.5 and R.sup.6 are each
independently selected from hydrogen, C.sub.1-8 alkyl, C.sub.3-6
cycloalkyl, phenyl; or R.sup.5 and R.sup.6 taken together with the
nitrogen to which they are attached represent a 5-6 membered
saturated ring,
(vii) OR.sup.7, where R.sup.7 is hydrogen, alkali metal, C.sub.1-8
alkyl, benzyl, or
(b) --Alk--OR.sup.8, where Alk is C.sub.1-2 alkylidene, and R.sup.8
is
(i) phenyl C.sub.1-6 alklycarbonyl,
(ii) C.sub.5-10 cycloalkylcarbonyl,
(iii) benzoyl,
(iv) C.sub.1-8 alkoxycarbonyl,
(v) aminocarbonyl, or C.sub.1-8 alkyl substituted
aminocarbonyl,
(vi) hydrogen, or
(vii) C.sub.1-8 alkyl,
(2) .dbd.CH--W--CO--R.sup.4 or .dbd.CH--W--OR.sup.8, where W is a
bond of C.sub.1-12 alkylidene and R.sup.4 and R.sup.8 have the same
meaning as above and R8 also is hydrogen or C.sub.1-20
alkylcarbonyl,
(3) ##STR11## where the dashed bond replaces the
17-.alpha.-hydrogen, (4) .alpha.-hydrogen and NHCOR.sup.9 where
R.sup.9 is C.sub.1-12 alkyl or NR.sup.5 R.sup.6 where R.sup.5 and
R.sup.6 have the same meaning as above,
(5) .alpha.-hydrogen and cyano,
(6) .alpha.-hydrogen and tetrazolyl, or
(7) keto;
or a pharmaceutically acceptable salt thereof; except compounds in
which:
(i) the B ring has a C.sub.5 -C.sub.6 double bond, R.sup.1 is
CH.sub.3, and R.sup.3 is keto, methoxycarbonyl, or acetyl; or
(ii) the A-nor ring has a C.sub.3 -C.sub.4 double bond and R.sup.3
is acetoxy or acetyl;
(iii) R.sup.1 is CH.sub.3 and R.sup.3 is acetoxy or acetyl; or
(iv) the A-nor ring has a C.sub.3 -C.sub.4 double bond and R.sup.1
is methyl; or
(v) the B ring has a C.sub.3 -C.sub.4 double bond and R.sup.3 is
.beta.-hydroxy.
Representative compounds whose synthesis and properties are
disclosed in the above issued US patents include the following and
pharmaceutically acceptable salts thereof:
4-methyl-4-aza-5.alpha.-8(14)-pregnen-3-one-(20R)-20-carboxylic
acid;
(20R)-hydroxymethyl-4-methyl-4-aza-5.alpha.-8(14)-pregnen-3-one;
4-methyl-4-aza-5.alpha.-8(14)-androsten-3-one-17.beta.-N,N-diisopropylcarbo
xamide;
17.beta.-(N,N-diisopropylcarboxamide)-estr-1,3,5(10)-triene-3-phosphonic
acid;
17.beta.-(N-tert-butylcarboxamide)-estr-1,3,5(10)-triene-3-phosphonic
acid;
17.beta.-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),16-tetraene-3-phosphon
ic acid;
17.beta.-(N-tert-butylcarboxamide)-estr-1,3,5(10),16-tetraene-3-phosphonic
acid;
17.beta.-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),6,8-pentaene-3-phospho
nic acid;
17.beta.-(N,N-diisopropylcarboxamide)-2-methyl-estr-1,3,5(10)triene-3-phosp
honic acid;
17.beta.-(N,N-diisopropylcarboxamide)-4-methyl-estr-1,3,5(10)-triene-3-phos
phonic acid;
17.beta.-(N-N-diisopropylcarboxamide)-estr-1,3,5(10),6-tetraene-3-phosphoni
c acid;
17.beta.-(N-N-diisopropylcarboxamide)-2-chloro-estr-1,3,5(10)-triene-3-phos
phonic acid;
17.beta.-(N-N-diisopropylcarboxamide)-4-chloro-estr-1,3,5(10)-triene-3-phos
phonic acid;
17.beta.-(N-butylcarboxamide)-estr-1,3,5(10)-triene-3carboxylic
acid;
17.beta.-(N-butylcarboxamide)-estr-1,3,5(10)16-tetraene-3-carboxylic
acid;
17.beta.-(N,N-diisopropylcarboxamide)-estr-1,3,5(10)-triene-3-phosphinic
acid;
17.beta.-(N-tert-butylcarboxamide)-estr-1,3,5(10)-triene-3-phosphinic
acid;
17.beta.-(N,N-diisoprPpylcarboxamide)-2-methyl-estr-1,3,5(10)-triene-3-phos
phinic acid;
17.beta.-(N,N-diisopropylcarboxamide)-4-methyl-estr-1,3,5(10)-triene-3-phos
phinic acid;
17.beta.-(N,N-diisopropylcarboxamide)-2-chloro-estr-1,3,5(10)-triene-3-phos
phinic acid;
17.beta.-(N,N-diisopropylcarboxamide)-4-chloro-estr-1,3,5(10)-triene-3-phos
phinic acid;
17.beta.-(N,N-diisopropylcarboxamide)-1,3,5(10),16-tetraene-3-phosphinic
acid;
17.beta.-(N-tert-butylcarboxamide)-estr-1,3,5(10),16-tetraene-3-phosphinic
acid;
17.beta.-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),6,8-pentaene-3-phosphi
nic acid;
17.beta.-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),6-tetraene-3-phosphini
c acid;
17.beta.-(N,N-diisopropylcarboxamide)-estr-1,3,5(10)-triene-3-phosphonic
acid;
17.beta.-(N-tert-butylcarboxamide)-estr-1,3,5(10)-triene-3-phosphonic
acid;
17.beta.-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),16-tetraene-3-phosphon
ic acid;
17.beta.-(N-tert-butylcarboxamide)-estr-1,3,5(10),16-tetraene-3-phosphonic
acid;
17.beta.-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),6,8-pentaene-3-phospho
nic acid;
17.beta.-(N,N-diisopropylcarboxamide)-2-methyl-estr-1,3,5(10)-triene-3-phos
phonic acid;
17.beta.-(N,N-diisopropylcarboxamide)-4-methyl-estr-1,3,5(10)-triene-3-phos
phonic acid;
17.beta.-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),6-tetraene-3-phosphoni
c acid;
17.beta.-(N,N-diisopropylcarboxamide)-2-chloro-estr-1,3,5(10)-triene-3-phos
phonic acid;
17.beta.-(N,N-diisopropylcarboxamide)-4-chloro-estr-1,3,5(10)-triene-3-phos
phonic acid;
17.beta.-(N,N-diisopropylcarboxamide)-estr-1,3,5(10)-triene-3-sulfonic
acid;
17.beta.-(N-tert-butylcarboxamide)-estr-1,3,5(10)-triene-3-sulfonic
acid;
17.beta.-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),16-tetraene-3-sulfonic
acid;
17.beta.-(N-tert-butylcarboxamide)-estr-1,3,5(10),16-tetraene-3-sulfonic
acid;
17.beta.-(N,N-diisopropylcarboxamide)-estr-1,3,5(10),6,8-pentaene-3-sulfoni
c acid;
17.beta.-(N,N-diisopropylcarboxamide)-2-methyl-estr-1,3,5(10)-triene-3-sulf
onic acid;
17.beta.-(N,N-diisopropylcarboxamide)-4-methyl-estr-1,3,5(10)-triene-3-sulf
onic acid;
17.beta.-(N,N-diisopropylcarboxamide)-2-chloro-estr-1,3,5(10)-triene-3-sulf
onic acid;
17.beta.-(N,N-diisopropylcarboxamide)-4-chloro-estr-1,3,5(10)-triene-3-sulf
onic acid;
17.beta.-(N,N-diisopropylcarboxamide)-androst-3,5-diene-3-phosphinic
acid;
17.beta.-(N-t-butylcarboxamide)-androst-3,5-diene-3-phosphinic
acid;
17.beta.-(N,N-diisopropylcarboxamide)-5.alpha.-androst-3-ene-3-phosphinic
acid;
17.beta.-(N,N-diisopropylcarboxamide)-5.alpha.-androst-2-ene-3-phosphinic
acid;
17.beta.-(N,N-diisopropylcarboxamide-androst-2,4-diene-3-phosphinic
acid;
methyl(17.beta.-N,N-diisopropylcarboxamide)-androst-3,5-diene-3-phosphinic
acid;
20.alpha.-(hydroxymethyl)-5.alpha.-pregn-3-ene-3-phosphinic
acid;
17.beta.-(N,N-diisopropylcarboxamide)-4-fluoro-5.alpha.-androst-3-ene-3-pho
sphinic acid;
20.alpha.-(hydroxymethyl)-4-fluoro-5.alpha.-pregn-3-ene-3-phosphinic
acid;
20.alpha.-(hydroxymethyl)-A-nor-5.alpha.-pregn-1-ene-2-phosphinic
acid;
17.beta.-(N,N-diisopropylcarboxamide)-5.alpha.-androst-1,3-diene-3-phosphin
ic acid;
17.beta.-(N,N-diisopropylcarboxamide)-5.alpha.-androstane-3.beta.-phosphini
c acid;
17.beta.-(N,N-diisopropylcarboxamide)-estr-3,5(10)-diene-3-phosphinic
acid;
17.beta.-(N,N-Diisopropylcarboxamide)-estr-3,5-diene-3-phosphinic
acid;
17.beta.-(N,N-Diisopropylcarboxamide)-androst-3,5-11-triene-3-phosphinic
acid.
20.alpha.-(hydroxymethyl)-5.alpha.-pregn-3-ene-3-carboxylic
acid;
N,N-diisopropyl-5.alpha.-androst-3-ene-17.beta.-carboxamide-3
carboxylic acid;
N,N-diisopropyl-androst-3,5-diene 17.beta.-carboxamide-3-carboxylic
acid;
17.beta.-(N,N-diisopropylcarboxamide)-4-fluoro-5.alpha.-androst-3-ene-3-car
boxylic acid;
20.alpha.-(hydroxymethyl)-4-fluoro-5.alpha.-pregn-3-ene-3-carboxylic
acid;
20.alpha.-(hydroxymethyl)-A-nor-5.alpha.-pregn-1-ene-2-carboxylic
acid;
17.beta.-N,N-diisopropylcarboxamide-5.alpha.-androst-1,3-diene-3-carboxylic
acid;
N-t-Butyl Androst-3,5-diene-17.beta.-carboxamide-3-carboxylic
acid;
N,N-Diisopropyl-5.alpha.-Androst-2-ene-17.beta.-carboxamide-3-carboxylic
acid;
N,N-Diisopropyl
Androst-2,4,-diene-17.beta.-carboxamide-3-carboxylic acid;
N,N-Diisopropyl 5.alpha.-Androstane-17.beta.-carboxamide carboxylic
acid;
N,N-Diisopropyl
Estr-3,5(10)-diene-17.beta.-carboxamide-3-carboxylic acid;
N,N,-Diisopropyl Estr-3,5-diene-17.beta.-carboxamide-3-carboxylic
acid;
20.alpha.(hydroxymethyl)-5.alpha.-pregn-3-ene-carboxylic acid
N,N-diisopropyl-5.alpha.-androst-3-ene-17.beta.-carboxamide-3-carboxylic
acid;
N,N-diisopropyl-androst-3,5-diene-17.beta.-carboxamide-3-carboxylic
acid;
17.beta.-(N,N-diisopropylcarboxamide)-4-fluoro-5.alpha.-androst-3-ene-3-car
boxylic acid;
17.beta.-(N,N-Diisopropylcarboxamide)-androst-3,5,11-triene-3-carboxylic
acid;
17.beta.-(N,N-Diisopropylcarboxamide)-androst-3,5-diene-3-thiocarboxylic
acid;
17.beta.-(N-t-Butylcarboxamide)-androst-3,5,11-triene-3-carboxylic
acid;
17.beta.-(N-t-Butylcarboxamide)-androst-3,5-diene-3-thiocarboxylic
acid,
N-t-butyl-androst-3,5-diene-17.beta.-carboxamide-3-carboxylic
acid,
N,N-diisopropyl-androst-3,5-diene-17.beta.-carboxamide-3-carboxylic
acid,
20.alpha.-(hydroxymethyl)-3-.alpha.-pregn-3-ene-3-carboxylic
acid,
20.alpha.-(hydroxymethyl)-4-fluoro-5-.alpha.-pregn-3-ene-3-carboxylic
acid,
3-carbomethoxy-N,N-diisopropyl-androst-3,5-diene-17.beta.-carboxamide,
17.beta.-N,N-diisopropylcarboxamide-5-.alpha.-androst-1,3-diene-3-carboxyli
c acid,
N,N-Diisopropyl
5-.alpha.-androst-2-ene-17.beta.-carboxamide-3-carboxylic acid,
N,N-diisopropyl androst-2-4-diene-17.beta.-carboxamide-3-carboxylic
acid,
N,N-diisopropyl
5-.alpha.-androstane-17.beta.-carboxamide-3.beta.-carboxylic acid,
and
N,N-diisopropyl
estr-3,5(10)-diene-17.beta.-carboxamide-3-carboxylic acid.
The benzoylaminophenoxy butanoic acid derivatives are of the
formula: ##STR12## wherein R' is hydrogen or alkyl of from 1 to 4
carbon atom(s); A is oxygen atom, sulfur atom or sulfinyl (SO)
group; both R.sup.1 's are methyl or chlorine, or the two R.sup.1
's and the carbon atoms of the benzene ring to which the two
R.sup.1 's are linked together are cyclopentane, cyclohexane or a
benzene ring; and
R.sup.2 represents a group of formula: ##STR13## wherein B is
oxygen, sulfur or a group of formula: NR.sup.11 wherein R.sup.11 is
hydrogen or alkyl of from 1 to 4 carbon atom(s),
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are,
independently, hydrogen, alkyl of from 1 to 4 carbon atom(s),
halogen, trifluoromethyl or cyclobutylmethyl,
m is 0 or 1,
n is an integer of from 1 to 5, and
R.sup.9 is a hydrogen, alkyl of from 1 to 5 carbon atom(s) or a
group of formula: ##STR14## wherein R.sup.12, R.sup.13, R.sup.14,
and R.sup.15 are, independently, hydrogen, alkyl of from 1 to 4
carbon atom(s), halogen, trifluoromethyl or cyclobutylmethyl, and 1
is an integer of from 1 to 4, and
R.sup.10 is a group of formula: ##STR15## wherein R.sup.12,
R.sup.13, R.sup.14, and R.sup.15 are, independently, hydrogen,
alkyl of from 1 to 4 carbon atom(s), halogen, trifluoromethyl or
cyclobutylmethyl, and 1' is an integer of from 1 to 4; or non-toxic
salts thereof.
Representative examples of each of these two classes of compounds
whose synthesis and properties are disclosed in the above cited US
issued patents include the following:
4-[2-(4-benzyloxy-2,3-dimethylbenzoylamino)phenoxy]butanoic
acid;
4-[2-[4-(2-methylbenzyloxy)-2,3-dimethylbenzoylamino]butanoic
acid;
4-[2-[4-(3-methylbenzyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoic
acid;
4-[2-[(4-methylbenzyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoic
acid;
4-[2-[4-(2,6-dimethylbenzyloxy)-2,3-dimethylbenzoyl-amino]phenoxy]butanoic
acid;
4-[2-[4-(4-ethylbenzyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoic
acid;
4-[2-[4-(4-propylbenzyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoic
acid;
4-[2-[4-(4-isopropylbenzyloxy)-2,3-dimethylbenzoyl-amino]phenoxy]butanoic
acid;
4-[2-[4-(4-isobutylbenzyloxy)-2,3-dimethylbenzoyl-amino]phenoxy]butanoic
acid;
4-[2-[4-(4-chlorobenzyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoic
acid;
4-[2-[4-(4-cyclobutylmethylbenzyloxy)-2,3-dimethylbenzoylamino]phenoxy]buta
noic acid;
4-[2-[4-(2-phenylethoxy)-2,3-dimethylbenzoylamino]phenoxy]butanoic
acid;
4-[2-[4-(3-phenylpropoxy)-2,3-dimethylbenzoylamino]phenoxy]butanoic
acid;
4-[2-[4-(4-phenylbutoxy)-2,3-dimethylbenzoylamino]phenoxybutanoic
acid;
4-[2-[4-(5-phenylpentyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoic
acid;
4-[2-[4-(1-(4-isobutylphenyl)ethoxy)-2,3-dimethylbenzoylamino]phenoxy]butan
oic acid;
4-[2-[4-(4-propylbenzyloxy)-2,3-dimethylbenzoylamino)phenylthio]butanoic
acid;
4-[2-[1-(4-isobutylphenyl)ethoxy)-2,3-dimethylbenzoylamino]phenylthio]butan
oic acid;
4-[2-[4-(4-propylbenzyloxy)-2,3-dimethylbenzoylamino]phenylsulfinyl)butanoi
c acid;
4-[2-[4-[N-(4-trifluoromethylphenylmethyl)amino)-2,3-dimethylbenzoylamino]p
henoxy]butanoic acid;
4-[2-[4-(4-isobutylbenzyloxy)-5,6,7,8-tetrahydronaphthalene-1-carbonylamino
)phenoxybutanoic acid;
4-[2-[4-(4-isobutylbenzyloxy)naphthalene-1-carbonylamino)phenoxy)butanoic
acid;
4-[2-[8-(4-isobutylbenzyloxy)-5,6,7,8-tetrahydronaphthalene-1-carbonylamino
)phenylthio]butanoic acid;
4-[2-[4-[bis(4-propylphenyl)methoxy]2,3-dimethylbenzoylamino)phenoxy]butano
ic acid;
4-[2-(4-diphenylmethoxy)-2,3-dimethylbenzoylamino)phenoxy]butanoic
acid;
4-[2-[4-[bis(4-propylphenyl)methylamino]-2,3-dimethylbenzoylamino]phenoxy]b
utanoic acid;
4-[2-[4-[bis-(4-propylphenyl)methylthio]-2,3-dimethylbenzoylamino]phenoxy]b
utanoic acid;
4-[2-[4-[N,N-bis(4-propylphenylmethyl)amino]-2,3-dimethylbenzoylamino]pheno
xy]butanoic acid;
4-[2-[4-[N,N-bis(4-trifluoromethylphenylmethyl)amino]-2,3-dimethylbenzoylam
ino]phenoxy]butanoic acid;
4-[2-[4-N-methyl-N-(5,6,7,8-tetrahydronaphth-1-yl]aminomethyl]-2,3-dimethyl
benzoylamino]phenoxy]-butanoic acid;
8-(p-pentylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-pentylbenzoyl)amino-2-(5-tetrazolyl)-6
chloro-1,4-benzodioxane;
8-(m-octylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(o-pentylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-butylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-hexylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-heptylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-octylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-nonylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-decylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-undecylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-dodecylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(m-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(o-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-butyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-nonyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-propoxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(o-decyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-isopentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-isohexyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-[p-(1-methylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(N-methyl-N-(p-octynyloxy)benzoyl])amino-2-(5-tetrazolyl)-1,4-benzodioxan
e;
8-(p-oxtyloxybenzoyl)amino-1,4-benzodioxane-2-carboxylic acid and
methyl ester thereof;
8-(p-isoheptyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-isooctyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-[p-(3,7-dimethyloctyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-7-carboxylic
acid and methyl ester thereof, and the like.
Also included as a 5.alpha.-reductase inhibitor in this invention
is a cinnamoylamide of the following formula: ##STR16## wherein
R.sup.2 and R.sup.3 each independently represents a hydrogen or
methyl group with the proviso that
(i) when R.sup.2 represents a methyl group, R.sup.3 represents
hydrogen and (R.sup.1)n represents a member selected from the group
consisting of 3-group, 4-pentyl group, 4-neopentyl group,
4-(2-ethylbutyl) group and 4-(2-methylpentyl) group, or
(ii) when R.sup.2 represents hydrogen, R.sup.3 represents a methyl
group and (R.sup.1)n represents a 3-pentyl group, or non-toxic
salts thereof.
Representative compounds include:
4-[2-(4-butylthio-.beta.-methylcinnamoylamino)phenoxy]butanoic
acid
4-[2-(4-cyclobutylmethy).beta.-methylcinnamoylamino)phenoxy]butanoic
acid
4-[2-(4-cyclohexylmethyl).beta.-methylcinnamoylamino)phenoxy]butanoic
acid
4-[2-(4-{4-phenylbutyl)-.beta.-methylcinnamoylamino)phenoxy]butanoic
acid
4-[2-(4-phenoxy-.beta.-methylcinnamoylamino)phenoxy]butanoic
acid
4-[2-(3-pentyl-.alpha.-methylcinnamoylamino)phenoxy]butanoic
acid
4-[2-(4-phenethyl-.alpha.-methylcinnamoylamino)phenoxy]butanoic
acid
4-[2-(3-pentyl-.beta.-methylcinnamoylamino)phenoxy]butanoic
acid
4-[2-(4-neopentyl]-.beta.-methylcinnamoylamino)phenoxy]butanoic
acid
4-[2-{4-(2-ethylbutyl)-.beta.-methylcinnamoylamino)phenoxy]butanoic
acid,
4-[2-{4-(2-methylpentyl)-.beta.-methylcinnamoylamino)phenoxy]butanoic
acid, and
4-[2-(2-fluoro-4-pentylexy-.beta.-methylcinnamoylamino)phenoxy]butanoic
acid.
Also included in this invention are fused benz(thio) amides of the
formula: ##STR17## wherein A represents a single bond or a group of
methylene, ethylene, trimethylene, tetramethylene, vinylene,
propenylene, butenylene, butadienylene or ethynylene group
optionally being substituted by one, two or three of straight or
branched alkyl group(s) of from 1 to 10 carbon atom(s) and/or
phenyl group(s);
B represents a heterocyclic ring of from 4 to 8 members containing
one, two or three hetero atom(s) selected from the group consisting
of oxygen, nitrogen and sulphur atom(s), wherein the said ring may
optionally be substituted by group(s) selected from oxo, thioxo
and/or hydroxy group(s) including a ring of formula: ##STR18## T
represents an oxygen atom or a sulphur atom; R.sup.1 represents a
group of general formula: ##STR19## (iv) a straight or branched
alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s),
wherein R.sup.5 and R.sup.6 independently represent a hydrogen atom
or a halogen atom or a straight or branched alkyl, alkenyl or
alkynyl group of from 1 to 20 carbon atom(s) being unreplaced or
replaced by one, two, three, four or five optional carbon atom(s),
by oxygen atom(s), sulphur atom(s), halogen atom(s), nitrogen
atom(s), benzene ring(s), thiophene ring(s), naphthalene ring(s),
carbocyclic ring(s) of from 4 to 7 carbon atom(s), carbonyl
group(s), carbonyloxy group(s), hydroxy group(s), carboxy group(s),
azido group(s) and/or nitro group(s);
R.sup.2 represents a hydrogen atom or a straight or branched alkyl
group of from 1 to 6 carbon atom(s);
R.sup.3 represents a hydrogen atom, a halogen atom, a hydroxy
group, a nitro group, a group of general formula: --COOR.sup.7,
wherein R.sup.7 represents a hydrogen atom or a straight or
branched alkyl group of from 1 to 6 carbon atom(s), or a straight
or branched alkyl, alkoxy or alkylthio group of from 1 to 6 carbon
atom(s);
R.sup.4 represents a group of general formula: ##STR20## wherein U
represents an oxygen atom or a sulphur atom, R.sup.8 represents a
hydrogen atom or a straight or branched alkyl group of from 1 to 6
carbon atom(s), n and m represent an integer of from 1 to 10,
respectively, p and q represent zero or an integer of from 1 to 10,
respectively, or non-toxic salts thereof.
Representative compounds include:
7-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)benzofuran,
7-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)benzofuran,
7-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)benzofuran,
7-(p-nonyloxybenzoyl)amino-2-)5-tetrazoyly)benzofuran,
7-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-benzofuran,
7-[p-(2E,7,-octadienyl)benzoyl]amino-2-(5-tetrazolyl)-benzofuran,
7-[p-(6-chlorohexyloxy)benzoyl]amino-2-(5-tetrazolyl)-benzofuran
and
7-(p-pentyicinnamoyl)amino-2-(5-tetrazolyl)benzofuran,
7-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1-benzofuran,
7-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1-benzofuran,
7-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1-benzofuran,
7-(p-nonyloxybenzoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1-benzofuran,
7-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1-benzofuran,
8[p-2E,7-octadienyloxy)benzoyl]amino-2-(5-tetrazolyl)quinoline,
8-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-quinoline,
8-[p-(6-chlorohexyloxy)benzoyl]amino-2-(5-tetrazolyl)-quinoline,
8-[p-(2E,7-octadienyloxy)benzoyl]amino-4-hydroxyquinoline-2-carboxylic
acid,
8-[p-(4-phenylbutoxy)benzoyl]amino-4-hydroxyquinoline-2-carboxylic
acid,
8-[p-[4-(2-thienyl)butoxy)benzoyl]amino-4-hydroxyquinoline-2-carboxylic
acid,
8-[p-(2E,7-octadienyloxy)benzoyl]amino-4-hydroxy-2-(tetrazolyl)quinoline,
8-[p-(4-(2-phenylbutoxy)benzoyl]amino-4-hydroxy-2-(5-tetrazolyl)quinoline
and,
8-(p-pentylcinnamoyl)amino-4-hydroxy-2-(5-tetrazolyl)quinoline
and,
4-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-1,3-benzodioxole,
4-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-1,3-benzodioxole,
4-[p-[4-(phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)1,3-benzodioxole,
4-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,3-benzodioxole,
9-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-3,4-dihydro-2H-1,5-benz
odioxepin,
9-[p-(2E,
7-octadienyloxy)benzoyl]amino-2-(5-tetrazolyl)-3,4-dihydro-2H-1,5-benzodio
xepin,
9-[p-(7-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-3,4-dihydro-2H-1,5-benzod
ioxepin,
8-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1,4-benzoxazine,
8-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-2,3-dihydro-1,4-benzoxa
zine and
8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1,4-benzoxazine,
8-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzothiopyr
an,
8-[p-(4-phenylbutoxy)benzol]amino-2-(5-tetrazolyl)-3,4-dihydro-2H-1-benzopy
ran,
8-[p-(7-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-3,4-dihydro-2H-1-benzopyr
an,
8-(p-pentylbenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8-(p-pentylbenzoyl)amino-4-oxo-4H-1-benzopyran-2-carboxylic acid
and ethyl ester thereof,
8-(p-hexylbenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8-(p-heptylbenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8-(p-octylbenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran
and
8-(p-nonylbenzoyl)amino-2-(5-tetrazolyl-4-oxo-4H-1-benzopyran
8-(p-butoxybenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8-(p-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8-(p-nonyloxybenzoyl)amino-2-(5tetrazolyl)-4-oxo-4H-1-benzopyran,
8-(p-octyloxybenzoyl
)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-6-fluoro-4-oxo-4H-1-benzopyran
8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-benzopyran
and
8-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-benzopyran
and
8p-(2E,7-octadienyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran
8-(p-geranyloxybenzoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8p-(2E-nonenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8[p-(2E-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8[p-(7-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8[p-(2E-heptenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8[p-(2E-hexenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8[p-(2E,7-octadienyloxy)benzoyl]amino-2-(5-tetrazolyl)-6-fluoro-4-oxo-4H-1-
benzopyran,
8[p-(2E-octenyloxy)benzoyl]amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-benzo
pyran,
8[p-(2E,7-octadienyloxy)benzoyl]amino-2-(5-tetrazolyl)-6-chloro-4-oxo-4H-1-
benzopyran,
8[p-(2-octynyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
thereof
8[p-(4-chlorobutoxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8[p-(5-chloropentyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran
8[p-(6-chlorohexyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8[p-(6-chlorohexyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8[p-(7-chloroheptyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran
8[p-(8-chlorooctyloxy)benzoyl]amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-be
nzopyran,
8[p-(7-chloroheptyloxy)benzoyl]amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-b
enzopyran and
8[p-(8-chlorooctyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8[p-(3-phenylpropoxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8[p-(3-phenyl-2E-propenyloxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benz
opyran,
8[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-benz
opyran,
8[p-[2-(2-naphthy)ethoxy]benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyr
an,
8[p-[2-(2-naphthyl)ethoxy])benzoyl]amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H
-1-benzopyran,
8[p-[3-(3,4-dichlorophenyl)propoxy]benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-
1-benzopyran,
8[p-[3-(3,4-dichlorophenyl)propoxy]benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-
1-benzopyran,
8[p-[3-(p-chlorophenyl)butoxy]benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-ben
zopyran,
8[p-[3-(p-chlorophenyl)butoxy]benzoyl]amino-6-methyl-2-(5-tetrazolyl)-4-oxo
-4H-1-benzopyran,
8[p-[3-(p-chlorophenyl)propoxy]benzoyl]amino-6-methyl-2-(5-tetrazolyl)-4-ox
o-4H-1-benzopyran,
8[p-[4-(2-thienyl)butoxy]benzoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyr
an,
8[p-[4-(2-thienyl)butoxy]benzoyl]amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1
-benzopyran,
8-(p-pentylcinnamoyl)amino-4-oxo-4H-1-benzopyran-2-carboxylic acid
and methyl ester thereof,
8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-6-methyl-4-oxo-4H-1-benzopyran,
8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-6-fluoro-4-oxo-4H-1-benzopyran,
8-(p-pentylcinnamoyl)amino-6-methyl-4-oxo-4H-1-benzopyran-2-carboxylic
acid and ethyl ester thereof,
8-(p-butylcinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8-(p-hexylcinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8-(p-heptylcinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8-cinnamoylamino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8-(p-hexyloxycinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8-(p-heptyloxycinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8-(p-isohexyloxycinnamoyl)amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran,
8[p-(2-octynyloxy)cinnamoyl]amino-4-oxo-4H-1-benzopyran-2-carboxylic
acid,
8[p-(5-chloropentyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyr
an,
8[p-(6-chlorohexyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyra
n,
8-(p-pentylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-pentylbenzoyl)amino-2-(5-tetrazolyl)-6
chloro-1,4-benzodioxane;
8-(m-octylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(o-pentylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-butylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-hexylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-heptylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-octylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-nonylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-decylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-undecylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-dodecylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(m-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(o-pentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-butyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-nonyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-propoxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-hexyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-heptyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(o-decyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-isopentyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-isohexyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-[p-(1-methylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(N-methyl-N-(p-octynyloxy)benzoyl])amino-2-(5-tetrazolyl)-1,4-benzodioxan
e;
8-(p-octyloxybenzoyl)amino-1,4-benzodioxane-2-carboxylic acid and
methyl ester thereof;
8-(p-isoheptyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-isooctyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-[p-(3,7-dimethyloctyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane;
8-(p-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-7-carboxylic
acid,
8-[p-(2E-octyloxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(3-butenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(3Z-hexenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2Z-octenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2E-nonenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[N-methyl-N-[p-(2E-cctenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodio
xane,
8-[p-(2E-hexenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(3E-heptenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2E-octenyloxy)benzoyl)amino-1,4-benzodioxane-2-carboxylic
acid and methyl ester thereof,
8-[p-(2E-heptenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(4-pentenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2E-decenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-geranyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2E,7-octadienyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2E-pentenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2E-butenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(3E-octenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(7-octenyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2E,4E-octadienyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane
and
8-[p-(2E-octadienyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2-octynyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2-octynyloxy)benzoyl]amino-1,4-benzodioxane-2-carboxylic acid
and methyl ester thereof and
8-[p-(2-isooctynyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane
8-(p-pentylthiobenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(m-pentylthiobenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane
8-(o-pentylthiobenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane
and
8-(p-heptylthiobenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane
8-[p-(6-chlorohexyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(5-chloropentyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(4-chlorobutoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(7-chloroheptyloxy)benzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(8-chlorooctyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(9-chlorononyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane
and
8-[p-(t-bromopentyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4,-benzodioxane-2-c
arboxylic acid and methyl ester thereof
8-[p-hexyloxymethyl)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane
8-[p-(cyclohexylmethoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(4-cyclohexylbutoxy)benozyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
and
8-[p-(2-cyclohexylethoxy)benzoyl')amino-2-(5-tetrazolyl)-1,4-benzodioxane,
and
8-[p-(p-butylphenyl)methoxybenoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(5-phenylpentyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(3-phenylpropoxy)
benzoyl')amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(p-propylphenyl)methoxybenzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane
8-[p-(3-phenyl-2-propenyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxan
e,
8-[p-(4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-1,
4-benzodioxane,
8-[p-(o-pentylphenyl)methoxybenzoylamino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(m-butylphenylmethoxybenzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-phenylmethoxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2-phenylethoxy)benzoyl')amino-2-(5-tetrazolyl)1,4-benzodioxane,
8-[p-4-phenylbutoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p[-2-(2-naphthyl)ethoxy]benzoyl')amino-2-(5-tetrazolyl)-1,4-benzodioxane
8-[p-[3-(p-chlorophenyl)propoxy]benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodio
xane and
8-[p-[4-(p-chlorophenyl)butoxy]benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodiox
ane,
8-[p-(5-methoxycarbonylpen,tyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzod
ioxane,
8-[p-(6-acetyloxyhexyloxy)benzoyl]amino-2-(5-tetrazxolyl)-1,4-benzodioxane,
8-[p-(6-hydroxyhexyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benozdioxane,
8-[p-(2E-octenoyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane
and
8-(p-octanoylbenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane
8-[p-(3-phenylthiopropoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(3-phenoxypropoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2-phenylthioethoxy)benzoyl')amino-2-(5-tetrazolyl)-1,4-benzodioxane
and
8-[p-(2-phenoxyethoxy)benzoyl')amino-2-(5-tetrazolyl)-1,4-benzodioxane
8-[p-[2-(3-thienyl)ethoxy]benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane
and
8-[p-[4-(2-thienyl)butoxy]benzoyl')amino-2-(5-tetrazolyl)-1,4-benodioxane
8-[p-(5-azidopenyloxy)benozyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(5-dimethylaminopentyloxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodiox
ane,
8-[p-(4-nitrobutoxy)benzoylamino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2-azidoethoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(4-azidobutoxy)benzoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2-octenoylamino)benzoyl')amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-pentyloxy-m-methoxybenzoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2E-octenyloxy)-m-chlorobenzoy]amino-2-(5-tetrazolyl)-1,4-benzodioxane
8-(2-naphthylcarbonyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-pentylcinnamoyl)amino-1,4-benzodioxane-2-carboxylic acid and
methyl ester thereof,
8-(p-heptylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[N-methyl-[N-(pentylcinnamoyl)]amino]-2-(5-tetrazolyl)-1,4-benzodioxane,
5-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-7-chloro-1,4-benzodioxane,
8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-6-chloro-1,4-benzodioxane,
8-(p-ethylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-propylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-butylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-6-methyl-1,4-benzodioxane,
8-(o-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(m-octylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-5-carboxylic
acid and methyl ester thereof,
5-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-8-carboxylic
acid and methyl ester thereof,
8-(p-hexylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-nonylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-6-carboxylic
acid and methyl ester thereof,
5-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane-7-carboxylic
acid and methyl ester thereof,
8-(p-octylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-decylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-P-isopropylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-isobutylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-isopentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-pentyl-2-methylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-pentyl-3-methylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane
and
8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)methyl-1,4-benzodioxane
8-(p-pentyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(m-pentyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(o-pentyloxycinnamoyl)amino-2-(5-tetrazoly)-1,4-benzodioxane,
8-(p-propoxycinnamoyl)amino-2-(5-tetrazolyl)-1,4,-benzodioxane,
8-(p-butoxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-octyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-hexyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-heptyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-isopentyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-isohexyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(1-methylbutoxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-isoheptyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-isooctyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-isohexyloxy-2-methylcinnamoyl)amino-2-(5-tetra-zolyl)-1,4-benzodioxane
and
8-(p-isohexyloxy-2-phenylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2E-octenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2-propenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(3-butenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(3Z-hexenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)1,4-benzodioxane,
8-[p-2Z-pentenyloxycinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2E-nonenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(3E-heptenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2E-heptenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2E-hexenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2E-pentenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)1,4-benzodioxane,
8-[p-(4-pentenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)1,4-benzodioxane,
8-[p-(2E-butenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane
and
8-[p-(2E-decenyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane
8-[p-(2-octynyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane
and
8-[p-(2-pentynyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-pentylthiocinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(m-pentylthiocinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane
and
8-(o-pentylthiocinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(6-chlorohexyloxy)cinnamoyl]amino-2-(5-tetrazolyl)1,4-benzodioxane,
8-[p-(4-chlorobutoxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(5-chloropentyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane
and
8-[p-(7-chloroheptyloxy)cinnamoyl')amino-2-(5-tetrazolyl)-1,4-benzodioxane
8-(p-isopentyloxymethyl-cinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-cyclohexylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-cyclohexylmethoxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(4-cyclohexylbutoxy)cinnamoyl')amino-2-(5-tetrazolyl)-1,4-benzodioxane
and
8-[p-(2-cyclohexylethoxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-phenylmethylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-phenylmethoxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(2-phenylethoxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(4-phenylbutoxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(5-phenylpentyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane
and
8-[p-(3-phenylpropoxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[p-(6-acetyloxyhexyloxy)cinnamoyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane
8-[p-[2-(2-thienyl)ethoxy)-cinnamoyl]-amino-2-(5-tetrazolyl)-1,4-benzodioxa
ne,
8-(m,p-dimethoxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(m-methoxy-p-pentyloxycinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane
and
8-(p-pentyloxy-m-chlorocinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane
8-[3-(5-indanyl)acryloyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane,
N-(2-hexadecenoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-(p-pentylphenylacetyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane
and
8-[3-(p-pentylphenyl)propionyl]amino-2-(5-tetrazolyl)-1,4-benzodioxane
8-(p-hexylphenylpropioloyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane,
8-[5-(p-propoxyphenyl)penta-2E,4E-dienoyl]amino-2-(5-tetrazolyl)-1,4-benzod
ioxane and
8-[5-(p-butylphenyl)penta-2E,4E-dienoyl]amino-2-(5-tetrazolyl)-1,4-benzodio
xane,
8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-14-dithianaphthalen
e and
5-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-2,3-dihydro-1,4-dithianaphthale
ne and sodium salts thereof.
Also included are aromatic 1,2-di(thio)ethers of the formula:
##STR21## wherein A is an 1,2-disubstituted aromatic ring;
preferably a benzene ring;
wherein
X is independently O, S, SO, or SO.sub.2 ;
R is H,
C.sub.1 -C.sub.4 alkyl,
phenyl or substituted phenyl,
halo,
haloalkyl,
hydroxy,
carboxy,
cyano,
C.sub.1 -C.sub.4 alkoxy,
C.sub.1 -C.sub.4 alkylthio,
C.sub.1 -C.sub.4 alkylsulfinyl,
C.sub.1 -C.sub.4 alkylsulfonyl,
nitro,
amino,
C.sub.1 -C.sub.4 mono or di-alkylamino;
R' and R" are independently
H,
halo,
C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy,
amino, or oxo, where CH--R' or CH--R" in the formula become
--C.dbd.O;
y is 1-6;
z is 6-20; and
wherein ##STR22## can independently represent substituted or
unsubstituted alkyl radicals or alkenyl radicals containing at
least one alkene bond;
and pharmaceutically acceptable salts and esters thereof.
The compounds of the instant invention are inhibitors of the human
testosterone-5.alpha.-reductase enzyme.
The scope of the compounds of the instant invention are described
by the above-described formula.
In the description of the formula the following terms are used
which are hereby defined:
X in the general formula above is O or S, preferably where one X is
O, and particularly where both Xs are O, e.g., resulting in the
catechol structure.
"C.sub.1 -C.sub.4 alkyl" includes linear or branched species, e.g.
methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl,
sec-butyl, t-butyl.
"C.sub.1 -C.sub.4 alkoxy" includes linear or branched species,
e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,
sec-butoxy, t-butoxy.
"Halo" includes fluoro, chloro, bromo or iodo.
"Substituted phenyl" includes phenyl substituted by one or more of
C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, or halo, and the
like, as defined above. representative examples include o, m-,
p-methoxy phenyl; 2,4-dimethoxyphenyl; 2-chloro-4-ethoxyphenyl;
3,5-dimethoxyphenyl; 2,4-dichlorophenyl; 2-bromo-4-methylphenyl,
o-fluorophenyl, and the like.
"Haloalkyl" includes C.sub.1 -C.sub.4 alkyl, defined above,
substitued with one or more "halo" as defined above and includes:
trifluoromethyl, 2,2-dichloroethyl and the like.
"C.sub.1 -C.sub.4 alkylthio" includes C.sub.1 -C.sub.4 alkyl,
defined above, substituted with at least one divalent thio (--S--)
grouping including; methylthio, ethylthio, isopropylthio,
n-butylthio, and the like.
"C.sub.1 -C.sub.4 alkylsulfinyl" includes C.sub.1 -C.sub.4 alkyl,
defined above, substituted with at least one --SO-- grouping
including; methylsulfinyl, ethylsulfinyl; isopropylsulfinyl, and
the like.
"C.sub.1 -C.sub.4 alkylsulfonyl" includes C.sub.1 -C.sub.4 alkyl,
defined above, substituted with at least one sulfonyl group,
--SO.sub.2 --, including; methylsulfonyl, ethylsulfonyl,
isopropylsulfonyl, n-butylsulfonyl, and the like.
"C.sub.1 -C.sub.4 mono or dialkyl amino" includes amino,
substituted with one or more C.sub.1 -C.sub.4 alkyl groups as
defined hereinabove, including: methylamino, ethylamino,
n-butylamino, t-butylamino, N,N-dimethylamino, N,N-diethylamino,
methyl-t-butylamino, and the like.
The R group or groups on the benzene ring can be present initially
in the process, such as in starting material I in Flow Chart A,
e.g. phenyl, methyl, methoxy, cyano, trifluoromethyl, carbomethoxy,
or added later by a conventional reaction, e.g. chloro, as by
chlorination, nitro by nitration, or created from a starting or
added functional group present, e.g. converting a nitro to an amino
group by catalytic reduction, then alkylating to a mono or
dialkylamine. An amino group can be subjected to diazotization to a
hydroxy group, which can be followed by methylation to a methoxy
group. Similarly, a hydroxy group can be converted to a thiol by
the analogous procedures described in J. Org. Chem. 31, pp
3980-3984 (1966) by Newman and Karnes, and J. Org. Chem. 31, pp 410
(1966) by Kwart, H. and Evans, E. S. The resulting thiol can be
alkylated to alkylthio, which can be oxidized to the corresponding
sulfoxide or sulfone. Preferred substituents are H, C.sub.1
-C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy and phenyl. These reactions
and sequences are conventional in the art and it will be obvious to
one skilled in the art to modify the benzene ring to arrive at an R
radical disclosed herein.
By the term "pharmaceutically acceptable salts and esters thereof"
is meant, salts and esters of the acid groups in the final molecule
which can be used as part of the human drug delivery system and
include the salts: sodium, potassium, calcium, ammonium,
substituted ammonium, quaternary ammonium, and esters: ethyl ester,
aceturate, besylate, edetate, phenpropionate, acetate, pamoate, and
esters which serye as "prodrug" formulations which will hydrolyze
in the body at physiological pH's to regenerate the acid, including
pivaloylates, e.g. pivoxetil and pivoxil, and Kanebo esters, and
the like. ##STR23## where y is 1-6, preferably 3, can contain at
least one R' substituent as defined above, and can be, e.g.,
##STR24## and the like.
An alkene bond can also be present in R' ##STR25## and the like.
##STR26## where z is 6-20, preferably 10-16, can contain at least
one R" substituent as defined above, and can be; e.g., ##STR27##
and the like.
An alkene bond can also be present in ##STR28## e.g., CH.sub.2
--CH.dbd.CH--(CH.sub.2).sub.8 --; --(CH.sub.2).sub.8
--CH.dbd.CH(CH.sub.2).sub.2 --; --(CH.sub.2).sub.9
--CH.dbd.CH--(CH.sub.2).sub.9 --; (CH.sub.2).sub.4
--CH.dbd.CH--(CH.sub.2).sub.4 --; and the like.
R' and R" can also be --NHCOCH.sub.3, which can be hydrolyzed to
amino by conventional acid or base hydrolysis in the final
molecule; R' and R" can also be oxo, obtained by, for example, HBr
addition to an alkene followed by conversion to an alcohol and
subsequent oxidation to the ketone.
Preferred is where one R' or R" is H and particularly preferred is
where both ##STR29## are alkyl.
Preferred compounds of the instant invention are given by the
following formulas; ##STR30## wherein one X is O and R, R', R", y
and z are defined above; and particularly preferred are the
compounds, ##STR31## wherein X is O or S and n is 10-16.
The compounds of the instant invention can be made by the procedure
outlined in the following Flowchart A-1. ##STR32##
As seen in Flow Chart A-1, Compound I is the starting substrate in
the invention process and is a 1,2-substituted benzene ring. X can
be independently O or S and "PG" represents a hydroxy or thio
protecting group which is inactive during Step (A) but can be
subsequently removed by, e.g. palladium on carbon catalyst in
ethanol under a pressurized H.sub.2 atmosphere.
Examples of "PG" protecting groups which are conventional and known
in the art (See "Protective Groups in Organic Synthesis" by
Theodora W. Greene--1981 --John Wiley--Chapter 2, "Protection for
the Hydroxyl Group, Including 1,2- and 1,3-Diols" pp. 16-87 and
Chapter 6 "Protection for the Thiol Group" pp. 193-218).
Representative examples of "PG" include: benzyl, p-methoxybenzyl,
p-halobenzyl; including p-chlorobenzyl, p-fluorobenzyl, and the
like. Other protective groups which are known will be obvious to
one skilled in the art to carry out the function of Step (A).
Representive examples of compounds useful as I in the instant
invention, include, but are not limited to the following:
2-(benzyloxy)-phenol,
2-benzyloxy-thiophenol,
2-(benzylthio)-phehol,
2-(benzylthio)thiophenol,
3-methoxy-2-benzyloxyphenol,
2-benzyloxy-4-methoxyphenol,
3-methyl-2-benzyloxyphenol,
2-benzyloxy-5-methylphenol,
2-benzyloxy-4-methylphenol,
2-benzyloxy-5-methylphenol,
2-benzyloxy-3,5-diisopropylphenol,
2-benzyloxy-3,5-di-t-butylphenol,
2-benzyloxy-4-t-butylphenol,
2-benzyloxy-3-ethylphenol,
2-benzyloxy-5-phenylphenol,
2-benzyloxy-4-methyl-1-thiophenol,
2-benzyloxy-5-trifluoromethyl-1-thiophenol,
2-benzyloxy-6-methoxy-1-thiophenol,
2-benzylthio-4-methyl-thiophenol,
2-benzylthio-5-methylsulfonyl-phenol, and the like.
Representative examples of II useful in the invention process where
L is a leaving group, e.g., halogen, including bromo, chloro, or
sulfonate, and the like, and R.sup.a is a C.sub.1 -C.sub.4 linear
or branched alkyl portion of the ester, including methyl, ethyl,
isopropyl, t-butyl, sec-butyl, and the like, and where R.sup.1 and
Y are or defined above, include, but are not limited to:
Br--CH.sub.2 --COOMe,
Cl--CH.sub.2 CH.sub.2 CH.sub.2 COOCH.sub.2 CH.sub.3,
Br--CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 COOMe,
Br--CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 COOEt,
Br--CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2
COOCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3,
Br--(CH.sub.2).sub.2 CH(CH.sub.3)COOMe,
Br--CH.sub.2 CH(CH.sub.3)CH.sub.2 COOEt,
Br--CH.sub.2 CH.sub.2 CH.sub.2 COOMe,
Br--CH.sub.2 CH(OCH.sub.3)CH.sub.2 COOCH(CH.sub.3).sub.2,
Cl--CH.sub.2 CH(OCH.sub.2 CH.sub.3)CH.sub.2 COOMe,
Br--CH.sub.2 CH(F)CH.sub.2 COOMe,
Cl--CH.sub.2 CH.sub.2 COOEt,
and the like.
In Step (A) the condensation of I and II to produce III takes place
in an non-hydroxylated polar organic solvent, e.g., acetone, ethyl
acetate, methylethylketone, dioxan, THF, diethylketone, and the
like, A proton acceptor is also present, e.g. potassium carbonate,
sodium bicarbonate, pyridine, triethylamine, and the like.
Generally, the reaction is carried out under an inert atomosphere,
e.g. dry nitrogen, and heated at reflux or allowed to sit for an
extended period of time at room temperature. Workup is
conventional.
In Step (B) the protecting group, "PG", is catalytically removed at
ambient temperature under a pressurized, hydrogen atmosphere in an
organic solvent to produce IV, being a phenol or thiophenol.
Operable catalysts include 5% Pd/C, and the like. The organic
solvent should be inert under the reaction conditions and includes
ethyl acetate, ethanol, methanol, dioxane, and the like.
Step (C) involves reacting IV with V to produce VI, the diester.
The reaction conditions are similar to those described in Step (A)
utilizing an inert organic solvent for the reactants and a proton
acceptor.
Representative examples of V useful in the invention are:
Br(CH.sub.2).sub.6 COOMe,
Br(CH.sub.2).sub.7 COOMe,
Br(CH.sub.2).sub.8 COOMe,
Br(CH.sub.2).sub.9 COOMe,
Br(CH.sub.2).sub.10 COOMe,
Br(CH.sub.2).sub.11 COOMe,
Cl(CH.sub.2).sub.12 COOEt,
Cl(CH.sub.2).sub.13 COOCH(CH.sub.3).sub.2,
Cl(CH.sub.2).sub.14 COOCH.sub.2 CH.sub.2 CH.sub.3,
Br--(CH.sub.2).sub.15 COOMe
Br--(CH.sub.2).sub.16 COOMe
Br(CH.sub.2).sub.16 COOCH.sub.2 CH.sub.3,
Br(CH.sub.2).sub.17 COOC(CH.sub.3).sub.3,
Br(CH.sub.2).sub.18 COOMe,
Br(CH.sub.2).sub.19 COOEt,
Br(CH.sub.2).sub.20 COOMe,
Br(CH.sub.2).sub.2 CH(CH.sub.3)--(CH.sub.2).sub.10 COOMe,
Br--CH.sub.2 CH(CH.sub.3)(CH.sub.2).sub.10 COOMe,
Br--CH.sub.2 CH.sub.3 CH(CH.sub.3)CH.sub.2 COOEt,
Br--CH.sub.2 CH(OCH.sub.3)(CH.sub.2).sub.7
COOCH(CH.sub.3).sub.2,
Cl--CH.sub.2 CH(OCH.sub.2 CH.sub.3)CH.sub.2 CH.sub.2 COOMe,
Br--CH.sub.2 CH(NHCOCH.sub.3)--(CH.sub.2).sub.10 --CH.sub.2
--COOMe, ##STR33## Br--CH.sub.2 --(CH.sub.2).sub.9
--CH.dbd.CH--COOMe, and the like.
In Step (D), the diester can be deesterified by aqueous basic
hydrolysis, e.g. NaOH in MeOH/H.sub.2 O to yield the diacid VII
upon acidification. ##STR34##
Flow Sheet B-1 illustrates the specific synthesis of 7.
As seen, 2-benzyloxyphenol 1, ethyl 4-bromobutyrate 2 and anhydrous
K.sub.2 CO.sub.3 in e.g., dry acetone are heated at reflux or
stirred for an extended period of time at room temperature, under a
nitrogen atmosphere to give product ethyl 4-(2-benzyloxyphenoxy)
butyrate 3, in Step (A).
A solution of 3 in e.g., ethyl acetate is catalytically
hydrogenated at room temperature under e.g. 40 psig of H.sub.2 in
the presence of a 5% Pd/C catalyst to yield ethyl
4-(2-hydroxyphenoxy) butyrate 4 in Step (B).
Step (C) comprises reacting 4 and methyl 12-bromododecanoate 5 with
potassium carbonate in acetone as in Step (A) to obtain the
monomethyl ester 6.
In Step (D), the diester 6 is de-esterified by e.g., 2.5 N NaOH in
MeOH/H.sub.2 O to yield the final product, diacid 7, upon
acidification.
Flow Sheet C-1 illustrates the synthesis of the sulfur analog of 7
as 7A. This analogous procedure uses substantially the same steps
as involved in Flow Sheet B.
It is also obvious from the above Flow Sheets that suitable
replacement compounds for II and 2 with other substituted and
unsubstituted halo alkyl esters, known in the art and described
herein, and that suitable replacement of V and 5 with other
bromoesters, available in the art and also described above will
yield all of the compounds within the scope of the instant
claims.
Representative examples of compounds produced by this process
include:
4-(2-(20-Carboxyeicosyloxy)phenoxy)butyric acid;
4-(2-(19-Carboxynonadecyloxy)phenoxy)butyric acid;
4-(2-(18-Carboxyoctadecyloxy)phenoxy)butyric acid;
4-(2-(17-Carboxyheptadecyloxy)phenoxy)butyric acid;
4-(2-(16-Carboxyhexadecyloxy)phenoxy)butyric acid;
4-(2-(15-Carboxypentadecyloxy)phenoxy)butyric acid;
4-(2-(14-Carboxytetradecyloxy)phenoxy)butyric acid;
4-(2-(13-Carboxytridecyloxy)phenoxy)butyric acid;
4-(2-(12-Carboxydodecyloxy)phenoxy)butyric acid;
4-(2-(11-Carboxyundecyloxy)phenoxy)butyric acid;
4-(2-(10-Carboxydecyloxy)phenoxy)butyric acid;
4-(2-(9-Carboxynqnyloxy)phenoxy)butyric acid;
4-(2-(8-Carboxyoctyloxy)phenoxy)butyric acid;
4-(2-(7-Carboxyheptyloxy)phenoxy)butyric acid;
4-(2-(6-Carboxyhexyloxy)phenoxy)butyric acid;
4-(2-(20-Carboxyeicosyloxy)phenylthio)butyric acid;
4-(2-(19-Carboxynonadecyloxy)phenylthio)butyric acid;
4-(2-(18-Carboxyoctadecyloxy)phenylthio)butyric acid;
4-(2-(17-Carboxyheptadecyloxy)phenylthio)butyric acid;
4-(2-(16-Carboxyhexadecyloxy)phenylthio)butyric acid;
4-(2-(15-Carboxypentadecyloxy)phenylthio)butyric acid;
4-(2-(14-Carboxytetradecyloxy)phenylthio)butyric acid;
4-(2-(13-Carboxytridecyloxy)phenylthio)butyric acid;
4-(2-(12-Carboxydodecyloxy)phenylthio)butyric acid;
4-(2-(11-Carboxyundecyloxy)phenylthio)butyric acid;
4-(2-(10-Carboxydecyloxy)phenylthio)butyric acid;
4-(2-(9-Carboxynonyloxy)phenylthio)butyric acid;
4-(2-(8-Carboxyoctyloxy)phenylthio)butyric acid;
4-(2-(7-Carboxyheptyloxy)phenylthio)butyric acid;
4-(2-(6-Carboxyhexyloxy)phenylthio)butyric acid;
4-(2-(20-Carboxyeicosylthio)phenoxy)butyric acid;
4-(2-(19-Carboxynonadecylthio)phenoxy)butyric acid;
4-(2-(18-Carboxyoctadecylthio)phenoxy)butyric acid;
4-(2-(17-Carboxyheptadecylthio)phenoxy)butyric acid;
4-(2-(16-Carboxyhexadecylthio)phenoxy)butyric acid;
4-(2-(15-Carboxypentadecylthio)phenoxy)butyric acid;
4-(2-(14-Carboxytetradecylthio)phenoxy)butyric acid;
4-(2-(13-Carboxytridecylthio)phenoxy)butyric acid;
4-(2-(12-Carboxydodecylthio)phenoxy)butyric acid;
4-(2-(11-Carboxyundecylthio)phenoxy)butyric acid;
4-(2-(10-Carboxydecylthio)phenoxy)butyric acid;
4-(2-(9-Carboxynonylthio)phenoxy)butyric acid;
4-(2-(8-Carboxyoctylthio)phenoxy)butyric acid;
4-(2-(7-Carboxyheptylthio)phenoxy)butyric acid;
4-(2-(6-Carboxyhexylthio)phenoxy)butyric acid;
4-(2-(20-Carboxyeicosylthio)phenylthio)butyric acid;
4-(2-(19-Carboxynonadecylthio)phenylthio)butyric acid;
4-(2-(18-Carboxyoctadecylthio)phenylthio)butyric acid;
4-(2-(17-Carboxyheptadecylthio)phenylthio)butyric acid;
4-(2-(16-Carboxyhexadecylthio)phenylthio)butyric acid;
4-(2-(15-Carboxypentadecylthio)phenylthio)butyric acid;
4-(2-(14-Carboxytetradecylthio)phenylthio)butyric acid;
4-(2-(13-Carboxytridecylthio)phenylthio)butyric acid;
4-(2-(12-Carboxydodecylthio)phenylthio)butyric acid;
4-(2-(11-Carboxyundecylthio)phenylthio)butyric acid;
4-(2-(10-Carboxydecylthio)phenylthio)butyric acid;
4-(2-(9-Carboxynonylthio)phenylthio)butyric acid;
4-(2-(8-Carboxyoctylthio)phenylthio)butyric acid;
4-(2-(7-Carboxyheptylthio)phenylthio)butyric acid;
4-(2-(6-Carboxyhexylthio)phenylthio)butyric acid;
3-(2-(16-Carboxyhexadecyloxy)phenoxy)propionic acid;
3-(2-(15-Carboxyisohexadecyloxy)phenoxy)butyric acid;
3-(2-(14-Carboxytetradecyloxy)phenoxy)butyric acid;
5-(2-(13-Carboxytridecyloxy)phenoxy)valeric acid;
5-(2-(12-Carboxydodecyloxy)phenoxy)valeric acid;
5-(2-(11-Carboxyisododecyloxy)phenoxy)valeric acid;
4-(2-(11-Carboxyundecyloxy)phenoxy)valeric acid;
4-(2-(10-Carboxydecyloxy)phenoxy)valeric acid;
4-(2-(9-Carboxynonyloxy)phenoxy)valeric acid;
6-(2-(9-Carboxynonyloxy)phenoxy)caproic acid;
6-(2-(8-Carboxyoctyloxy)phenoxy)caproic acid;
6-(2-(7-Carboxyisooctyloxy)phenoxy)caproic acid;
7-(2-(7-Carboxyheptyloxy)phenoxy)enanthic acid;
7-(2-(6-Carboxyhexyloxy)phenoxy)enanthic acid;
7-(2-(5-Carboxyisohexyloxy)phenoxy)enanthic acid;
2-(2-(12-Carboxydodecylthio)phenoxy)acetic acid;
2-(2-(11-Carboxydecylthio)phenoxy)acetic acid;
2-(2-(10-Carboxydecylthio)phenoxy)acetic acid;
3-(2-(9-Carboxynonyloxy)phenylthio)propionic acid;
3-(2-(12-Carboxydodecyloxy)phenylthio)propionic acid;
3-(2-(11-Carboxyundecyloxy)phenylthio)propionic acid;
3-(2-(11-Carboxyundecyloxy)phenylthio)butyric acid;
3-(2-(11-Carboxyundecylthio)-4-methyl-phenylthio)butyric acid;
3-(2-(12-Carboxydodecylthio)phenylthio)butyric acid;
5-(2-(11-Carboxyundecylthio)phenylthio)valeric acid;
5-(2-(10-Carboxydecyloxy)phenylthio)valeric acid;
5-(2-(9-Carboxynonyloxy)phenylthio)valeric acid;
3-(2-(12-Carboxydodecyloxy)phenylthio)valeric acid;
3-(2-(11-Carboxydecyloxy)phenylthio)valeric acid;
3-(2-(10-Carboxydecyloxy)phenylthio)valeric acid;
6-(2-(9-Carboxynonylthio)phenylthio)caproic acid;
6-(2-(12-Carboxydodecyloxy)phenylthio)caproic acid;
6-(2-(11-Carboxyundecyloxy)phenylthio)caproic acid;
6-(2-(11-Carboxyundecyloxy)-3-methylphenylthio)-enanthic acid;
7-(2-(11-Carboxyundecyloxy)-4-methylphenylthio)-enanthic acid;
7-(2-(12-Carboxydodecylthio)phenoxy)enanthic acid;
4-(2-(11-Carboxyundecyloxy)4-methyl-phenoxy)butyric acid;
4-(2-(10-Carboxydecyloxy)3-methylphenoxy)butyric acid;
4-(2-(9-Carboxynonyloxy)5-methylphenoxy)butyric acid;
4-(2-(12-Carboxydodecyloxy)6-methylphenoxy)butyric acid;
4-(2-(12-Carboxydodecyloxy)6-methylphenoxy)butyric acid;
4-(2-(11-Carboxyundecylthio)-3-(methylthio)phenoxy)-valeric
acid;
4-(2-(11-Carboxyundecylthio)-3-(methylsulfonyl)phenoxy)butyric
acid;
4-(2-(11-Carboxyundecyloxy)-4-(methylsulfonyl)phenoxy)butyric
acid;
4-(2-(12-Carboxydodecyloxy)5-ethyl-phenoxy)butyric acid;
4-(2-(11-Carboxyundecyloxy)4-phenylphenoxy)butyric acid;
4-(2-(10-Carboxydecyloxy)-3,5-dimethylphenoxy)butyric acid;
4-(2-(9-Carboxynonyloxy)-4-fluoro-phenoxy)butyric acid;
4-(2-(12-Carboxydodecyloxy)-5-(trifluoromethyl)-phenoy)butyric
acid;
4-(2-(12-Carboxydodecylthio)-5-nitrophenoxy)butyric acid;
4-(2-(11-Carboxyundecylthio)-4-methylphenoxy)valeric acid;
4-(2-(11-Carboxyundecylthio)-3,5-di-methylphenoxy)-butyric
acid;
4-(2-(12-Carboxydodecyloxy)-4-(dimethylamino)phenoxy)-butyric
acid;
4-(2-(11-Carboxyundecyloxy)-5-(ethylamino)phenoxy)-butyric
acid;
2-(2-(9-Carboxynonyloxy)phenoxy)propionic acid;
3-(2-(12-Carboxydodecyloxy)phenoxy)-3-methylpropionic acid;
4-(2-(10-Carboxydecyloxy)phenylthio)-3-methoxy-butyric acid;
4-(2-(9-Carboxynonyloxy)phenylthio)-3-ethoxy-butyric acid;
4-(2-(11-Carboxyundecyloxy)phenoxy)but-2-enoic acid;
4-(2-(9-Carboxynonyloxy)phenoxy)-2-butenoic acid;
4-(2-(11-Carboxy-2-methylundecyloxy)phenoxy)butyric acid;
4-(2-(11-Carboxyundecyl-7-ene-oxy)phenoxy)butyric acid;
4-(2-(13-Carboxy-2-methylene-tri-decyloxy)phenoxy)-butyric
acid;
4-(2-(11-Carboxyundecyloxy)phenylsulfonyl)butyric acid;
4-(2-(11-Carboxyundecyloxy)phenylsulfinyl)butyric acid;
4-(2-(11-Carboxyundecylsulfinyl)phenoxy)butyric acid;
4-(2-(11-Carboxyundecylsulfonyl)phenoxy)butyric acid;
4-(2-(11-Carboxyundecylsulfinyl)phenylsulfinyl)butyric acid;
4-(2-(11-Carboxyundecylsulfonyl)phenylsulfonyl)butyric acid; and
the like.
Also included as a 5.alpha.-reductase inhibitor in this invention
is an agent for the treatment of prostatic cancer in combination
with flutamide is of the following formula: ##STR35## wherein A is
an 1,2-disubstituted aromatic ring selected from
(a) benzene, 1,2-disubstituted naphthalene;
(b) 5-6 membered heteroaromatic ring, containing 1-2 N atoms, 1 S
or 0 atom, or combination thereof;
D and E are independently --COOH, --CONH.sub.2, CONHR.sub.b,
COOR.sub.b, SO.sub.2 OH, SO.sub.3 (OH), SO.sub.2 NH.sub.2,
--SSO.sub.2 ONa, PH(O)(OH), P(O)(OH).sub.2 ;
X is O, S, SO or SO.sub.2 ;
R is H,
C.sub.1 -C.sub.4 alkyl,
phenyl or substituted phenyl,
halo,
haloalkyl,
hydroxy,
carboxy,
cyano,
C.sub.1 -C.sub.4 alkoxy,
C.sub.1 -C.sub.4 alkylthio,
C.sub.1 -C.sub.4 alkylsulfinyl,
C.sub.1 -C.sub.4 alkylsulfonyl,
nitro,
amino,
C.sub.1 -C.sub.4 mono or di-alkylamino;
R' and R" are independently
H
halo,
C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy,
amino, or oxo, where CH--R' or CH--R" in the formula become
--C.dbd.O;
R.sub.a is H, C.sub.1 -C.sub.4 alkyl;
R.sub.b is C.sub.1 -C.sub.12 alkyl, phenyl or phenyl C.sub.1
-C.sub.4 alkyl;
y is 1-6;
z is 6-20; and
wherein ##STR36## can independently represent substituted or
unsubstituted alkyl radicals or alkenyl radicals containing at
least one alkene bond;
and pharmaceutically acceptable salts and esters thereof.
The compounds of the instant invention are inhibitors of the human
testosterone-5.alpha.-reductase
The scope of the compounds of the instant invention are described
by the above-described formula.
In the description of the formula the following terms are used
which are hereby defined:
X is preferably O or S, and particularly preferred is O.
"C.sub.1 -C.sub.4 alkyl" includes linear or branched species, e.g.
methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl,
sec-butyl, t-butyl and "C.sub.1 -C.sub.12 alkyl" includes, alkyl up
to 12 cartons including n-octyl, t-decyl, n-dodecyl.
"Phenyl C.sub.1 -C.sub.4 alkyl" includes benzyl, 2-phenethyl and
the like.
"C.sub.1 -C.sub.4 alkoxy" includes linear or branched species,
e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,
sec-butoxy, t-butoxy.
"Halo" includes fluoro, chloro, bromo or iodo.
By the term "heteroaromatic ring" as used herein is meant a 5-6
membered ring, containing 1-2 N-atoms, 1 S or O atom, or
combination thereof, and includes: pyridine, thiophene, furan,
imidazole, 1,3-thiazole, 1,3-oxazole, 1,2,3-thiadiazole, and the
like. The limitation here being that the 1,2-disubstitution occurs
on only ring carbons of the heteroaromatic ring. Preferred
heteroaromatic rings are pyridine, furan and thiophene.
"Substituted phenyl" includes phenyl substituted by one or more of
C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, or halo, and the
like, as defined above; representative examples include o, m-,
p-methoxy phenyl; 2,4-dimethoxyphenyl; 2-chloro-4-ethoxyphenyl;
3,5-dimethoxyphenyl; 2,4-dichlorophenyl; 2-bromo-4-methylphenyl,
o-fluorophenyl, and the like.
"Haloalkyl" includes C.sub.1 -C.sub.4 alkyl, defined above,
substitued with one or more "halo" as defined above and inlcudes:
trifluoromethyl, 2,2-dichloroethyl and the like.
"C.sub.1 -C.sub.4 alkylthio" includes C.sub.1 -C.sub.4 alkyl,
defined above, substituted with at least one divalent thio (--S--)
grouping including; methylthio, ethylthio, isopropylthio,
n-butylthio, and the like.
"C.sub.1 -C.sub.4 alkylsulfinyl" includes C.sub.1 -C.sub.4 alkyl,
defined above, substituted with at least one --SO-- grouping
including; methylsulfinyl, ethylsulfinyl; isopropylsulfinyl, and
the like.
"C.sub.1 -C.sub.4 alkylsulfonyl" includes C.sub.1 -C.sub.4 alkyl,
defined above, substituted with at least one sulfonyl group,
--SO.sub.2 --, including; methylsulfonyl, ethylsulfonyl,
isopropylsulfonyl, n-butylsulfonyl, and the like.
"C.sub.1 -C.sub.4 mono or dialkyl amino" includes amino,
substituted with one or more C.sub.1 -C.sub.4 alkyl groups as
defined hereinabove, including: methylamino, ethylamino,
n-butylamino, t-butylamino, dimethylamino, diethylamino,
methyl-t-butylamino, and the like.
The R group or groups on the benzene or heteroaromatic ring can be
present initially in the process, e.g. phenyl, methyl, methoxy,
cyano carbomethoxy, trifluoromethyl, (as in the starting
o-nitrophenol 1 in Flow Chart A) or added later by a conventional
reaction, e.g. chloro, as by chlorination, nitro by nitration, or
created from a starting or added functional group present, e.g.
converting a later added nitro group to an amino group by catalytic
reduction, then alkylating to a mono or dialkylamine. An amino
group can be subjected to diazotization to a hydroxy group, which
can be followed by methylation to a methoxy group. Similarly, a
hydroxy group can be converted to a thiol by the analogous
procedures described in J. Org. Chem. 31, pp 3980-3984 (1966) by
Newman and Karnes, and J. Org. Chem. 31, pp 410 (1966) by Kwart, H.
and Evans, E. S. The resulting thiol can be alkylated to alkylthio,
which can be oxidized to the corresponding sulfoxide or sulfone.
Preferred substituents are H, C.sub.1 -C.sub.4 alkyl, C.sub.1
-C.sub.4 alkoxy and phenyl. These reactions and sequences are
conventional in the art and it will be obvious to one skilled in
the art to modify the benzene ring to arrive at an R radical
disclosed herein.
By the term "pharmaceutically acceptable salts and esters thereof"
is meant, salts and esters of the acid groups in the final molecule
which can be used as part of the human drug delivery system and
include the salts: sodium, potassium, calcium, ammonium,
substituted ammonium, quaternary ammonium, and esters: ethyl ester,
aceturate, besylate, edetate, phenpropionate, acetate, pamoate, and
esters which serve as "prodrug" formulations which will hydrolyze
in the body at physiological pH's to regenerate the acid, including
pivaloylates, e.g. pivoxetil and pivoxil, and Kanebo esters, and
the like. ##STR37## where y is 1-6, preferably 3, can contain at
least one R' substituent as defined above, and can be alkyl, e.g.,
##STR38## and the like.
An alkene bond can also be present in ##STR39## e.g., --CH.sub.2
--CH.dbd.CH;--CH.sub.2 --CH.dbd.CH--CH.sub.2 ; --CH.sub.2
--CH.sub.2 --CH.dbd.CH; --(CH.sub.2).sub.3 --CH.dbd.CH, and the
like. ##STR40## where z is 6-20, preferably 8-14, can contain at
least one R" substituent as defined above, and can be alkyl; e.g.,
##STR41## and the like.
An alkene bond can also be present in ##STR42## e.g., --CH.sub.2
--CH.dbd.CH--(CH.sub.2).sub.8 --; --(CH.sub.2).sub.8
--CH.dbd.CH--(CH.sub.2).sub.2 --; --(CH.sub.2).sub.9
--CH.dbd.CH--(CH.sub.2).sub.9 --; (CH.sub.2).sub.4
--CH.dbd.CH--(CH.sub.2).sub.4 --; and the like.
Preferred is where one R' or R" is H and particularly preferred is
where both ##STR43## are alkyl.
Representative compounds of the instant invention within the above
general formula are given by the following, structures;
##STR44##
Particularly preferred are the following compounds: ##STR45## where
X is O or S and R, R', R", y and z are as defined above.
Preferred compounds within this class are: ##STR46## where X is O
or S, and n is 8-14.
Also preferred compound are within these classes are: ##STR47##
where n is 8-14. ##STR48## were n is 8-14.
The compounds of the instant invention can be made by the
procedures outlined in the following Flowcharts. ##STR49##
As seen in Flow Chart A-2, o-nitrophenol 1, ethyl 4-bromobutyrate 2
and anhydrous K.sub.2 CO.sub.3 in e.g., dry acetone are heated at
reflux or stirred for an extended period of time at room
temperature, under a nitrogen atmosphere to product ethyl
4-(2-nitrophenoxy) butyrate 3, in Step (A).
A solution of 3 in e.g., ethyl acetate is catalytically
hydrogenated at room temperature under e.g. 40 psig of H.sub.2 in
the presence of a 5% Pd/C catalyst to yield ethyl
4-(2-aminophenoxy)butyrate 4 in Step (B).
Step (C) comprises reacting diethyl dodecanoate 5 with barium
hydroxide octahydrate in methanol at ambient temperature to obtain
the monomethyl ester 6.
In Step (D) the mono ester mono acid 6 is refluxed with thionyl
chloride for about 5 hours to produce the mono acid chloride, mono
methyl ester 7.
Step (E) comprises the reaction of the mono acid chloride 7 with
the amine 4 at e.g., 0-10.degree. C. in e.g., dry ether in the
presence of a hydrogen acceptor e.g., triethylamine, to produce the
amide 8.
In Step (F), the ether-amide diester 8 is de-esterified by e.g.,
2.5 N NaOH in MeOH/H.sub.2 O to yield after acidification the final
product, diacid 9.
Flow Chart B-2 illustrates the synthesis of the corresponding thio
compounds.
Step (G) illustrates the reaction of o-aminobenzenethiol with ethyl
4-bromobutyrate which can be carried out in e.g., dry
dimethoxyethane, under dry N.sub.2, in the presence of a proton
acceptor, e.g., dry powdered K.sub.2 CO.sub.3, to produce 11.
Step (H) illustrates the acylation of the amino group of 11 with
ethyl 11-bromoundecanoate in a dry solvent, e.g., dry ether, at
0.degree. C. in the presence of an acid acceptor, e.g.,
pyridine.
Step (I) illustrates the hydrolysis of the diester to the final
diacid 13, which can be accomplished with, e.g., NaOH/MeOH.
As seen in Flow Chart C-2, o-nitrophenol is benzylated under the
same conditions as in Step (A).
Step (K) shows the reduction of the nitro group using e.g., Raney
Ni in ethanol/NH.sub.3 under 40 psig H.sub.2.
Step (L) shows the trifluoroacetylation of 24 using e.g.,
trifluoroacetic anhydride in dry ether and powdered dry sodium
carbonate.
Step (M) shows the N-methylation which can be accomplished using,
e.g., methyl iodide in dry acetone and dry powdered KOH followed by
removal of the N-trifluoroacetyl group with MeOH/H.sub.2 O.
Step (N) shows the N-acylation of 27, using an acid chloride, e.g.,
7, in e.g., dry methylene chloride and pyridine at 0.degree. C.
Step (O) shows the debenzylation of 28, which can be accomplished
by e.g., 10% Pd/C in MeOH under a H.sub.2 atmosphere.
Step (P) shows the O-alkylation of 29 using e.g., ethyl
4-bromobutyrate and K.sub.2 CO.sub.3 in anhydrous acetone.
Step (Q) shows hydrolysis of the diester 30 to the diacid 31 by
hydrolysis as e.g., described for Step (F).
Flow Chart D-2 shows the production of phosphonate type esters and
acids.
Step (R) shows the condensation of 4 with 11-bromoundecanoic acid
in anhydrous methylene chloride using N,N'-dicyclohexylcarbodiimide
and 4-dimethylaminopyridine to produce the important bromo
intermediate 32.
Step (S) shows the reaction of 32 with triethylphosphite at e.g.,
180.degree. C. under N.sub.2 to produce the phosphonate ester
33.
Step (T) converts 33 via bromotrimethylsilane to the monoacid
34.
Step (U) uses the similar hydrolysis conditions of Step (F) to
produce the phosphoniccarboxylic diacid 35.
The corresponding phosphinic acids can be analogously made from 32
by known procedures in the art.
Flow Chart E-2 illustrates the synthesis of the sulfonic acid types
of the invention compounds.
Step (V) shows reaction of the intermediate 32 with thiourea in
EtOH/H.sub.2 O under N.sub.2 at 90.degree. C. to yield the
isothiouronium salt 36.
Step (W) shows the reaction of 32 with sodium thiosulfate under the
conditions of Step (V) to yield the thiosulfate ester 37.
Further oxidation of esters 36 or 37 via the Showell or Ziegler
procedures described in Step W in the examples yields the
corresponding sulfonic acid 38.
The corresponding sulfinic acid can be prepared from 36 by the
procedure of J. M. Sprague and T. B. Johnson, JACS 59, 2440
(1937).
The corresponding sulfonamide can be produced from the sulfonic
acid 38, by protecting, e.g., the carboxylic acid via an ester,
converting the sulfonic acid to a sulfonyl chloride, treating the
sulfonyl chloride with ammonia and then hydrolyzing the protected
carboxylic ester to the corresponding acid.
Flow Chart F-2 shows the corresponding synthesis of the pyridine
analogs of 8 and 9.
In Step (X), the nitrohydroxy pyridine is O-alkylated first using
conditions analogous to Step (A) to produce 40.
Step (Y) shows reducing the nitro group in the same manner as
described for Step (B).
Step (Z) shows acylating the amino group in the same manner as
described for 8 in Step (E) to produce the diester 42. Hydrolysis
produces the diacid 43.
Flow Chart G-2 shows the production of some amides 46 of the
invention.
In Step (AA), o-aminophenol is reacted directly with 7 under the
conditions of Step (E) to produce the N-acylated phenol 44.
In Step (BB), O-alkylation of 44 as carried out using
4-bromobutyronitrile under conditions similar to Step (A), produces
45.
Step (CC) shows the hydrolysis of the nitrile to the amide 46 using
MnO.sub.2 in methylene chloride.
Flow Chart H-2 illustrates an alternate route to 9 by starting with
o-aminophenol, acylating to produce 44, then reacting 44 under the
conditions of Step (A) to produce 8, then hydrolysis using Step (F)
to yield 9.
Thus, by using the above described methods in the Flow Charts and
the reaction starting materials and reagents described herein, all
of the compounds described and encompassed by the claim can be
synthesized by one skilled in the art.
It is obvious that other nitrophenols can be substituted for 1 in
Flow Charts A-2 and C-2 to provide the scope of the compounds
covered by this invention and include the following:
2-nitrophenol
2-nitro-6-methylphenol
2-nitro-5-methylphenol
2-nitro-4-methylphenol
2-nitro-3-methylphenol
2-nitro-4-phenylphenol
2-nitro-5-phenylphenol
2-nitro-4-chlorophenol
2-nitro-4-fluorophenol
2-nitro-4-trifluoromethylphenol
2-nitro-4-hydroxyphenol
2-nitro-4-methoxyphenol
2-nitro-6-ethoxyphenol
2-nitro-4-methylthio-phenol
2-nitro-4-methylsulfinylphenol
2-nitro-4-methylsulfonylphenol
4-nitro-3-hydroxypyridine
3-nitro-4-hydroxy-5-methylpyridine
3-nitro-4-hydroxy-6-methylpyridine
2-methyl-3-nitro-4-hydroxypyridine
2-hydroxy-3-nitro-5-phenylpyridine
2-nitro-3-hydroxy-5-phenylpyridine
2-hydroxy-3-nitro-5-chloropyridine
2-nitro-3-hydroxy-5-trifluoromethylpyridine
2-methoxy-4-nitro-5-hydroxypyridine
3-nitro-4-hydroxy-5-ethoxypyridine
2-methylthio-4-nitro-5-hydroxypyridine
2-nitro-3-hydroxy-thiophene
3-nitro-4-hydroxy-thiophene
3-hydroxy-2-nitro-5-methyl-thiophene
3-hydroxy-2-nitro-4-methyl-thiophene
2-hydroxy-3-nitro-5-phenyl-thiophene
2-nitro-3-hydroxy-4-phenyl-thiophene
2-hydroxy-3-nitro-4-chlorothiophene
2-hydroxy-3-nitro-4-fluorothiophene
and the like.
It is obvious that suitable replacement compounds for 2 with other
halo alkyl esters, known in the art, and that suitable replacement
of 6 with other diesters, available in the art, will yield all of
the ether-amide derivatives within the scope of the claims.
Representative examples of 2 useful in the invention process
include, but are not limited to:
Br--CH.sub.2 --COOMe,
Cl--CH.sub.2 CH.sub.2 CH.sub.2 COOCH(CH.sub.3).sub.3,
Br--CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 COOMe,
Br--CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 COOEt,
Br--CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2
COOCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3,
Br--CH.sub.2 CH(CH.sub.3)COOMe,
Br--CH.sub.2 CH(CH.sub.3)CH.sub.2 COOEt,
Br--CH.sub.2 CH.sub.2 CH.sub.2 COOMe,
Br--CH.sub.2 CH(OCH.sub.3)CH.sub.2 COOCH(CH.sub.3).sub.2,
Cl--CH.sub.2 CH(OCH.sub.2 CH.sub.3)CH.sub.2 COOMe,
Br--CH.sub.2 CH(F)CH.sub.2 COOMe,
and the like.
Representative examples of other compounds substitutable for 6 and
useful in the invention are:
HOOC(CH.sub.2).sub.6 COOMe,
HOOC(CH.sub.2).sub.7 COOMe,
HOOC(CH.sub.2).sub.8 COOMe,
HOOC(CH.sub.2).sub.9 COOMe,
HOOC(CH.sub.2).sub.10 COOMe,
HOOC(CH.sub.2).sub.11 COOMe,
HOOC(CH.sub.2).sub.12 COOEt,
HOOC(CH.sub.2).sub.13 COOCH(CH.sub.3).sub.2,
HOOC(CH.sub.2).sub.14 COOCHCH.sub.2 CH.sub.3,
HOOC(CH.sub.2).sub.15 COO(CH.sub.2).sub.3 CH.sub.3,
HOOC(CH.sub.2).sub.16 COOCH.sub.3,
HOOC(CH.sub.2).sub.17 COOCH.sub.3,
HOOC(CH.sub.2).sub.18 COOMe,
HOOC(CH.sub.2).sub.19 COOEt,
HOOC(CH.sub.2).sub.20 COOPh,
HOOC(CH.sub.2).sub.10 COOCH.sub.2 Ph,
HOOCCH(CH.sub.3)--(CH.sub.2).sub.10 COOMe,
HOOC--CH.sub.2 CH--(CH.sub.3)(CH.sub.2).sub.10 COOMe,
HOOC--CH.sub.2 CH.sub.3 CH(CH.sub.3)CH.sub.2 COOEt, ##STR50##
HOOC--CH.sub.2 CH(OCH.sub.3)(CH.sub.2).sub.7 COOCH(CH.sub.3).sub.2,
where Ph is phenyl,
and the like.
Representative examples of compounds produced by this process
include those in the following list.
The nomenclature used herein for the acid radicals is:
P(O)(OH).sub.2, phosphono;
--COOH, carboxy;
--CONH.sub.2, aminocarbonyl;
--SO.sub.3 H, sulfo;
--SO.sub.2 H, sulfino;
--SSO.sub.3 H, thiosulfato, as the sodium salt.
4-(2-(20-Carboxyeicosanoylamino)phenoxy)butyric acid;
4-(2-(19-Carboxynonadecanoylamino)phenoxy)butyric acid;
4-(2-(18-Carboxyoctadecanoylamino)phenoxy)butyric acid;
4-(2-(17-Carboxyheptadecanoylamino)phenoxy)butyric acid;
4-(2-(16-Carboxyhexadecanoyl-N-methylamino)phenoxy)-butyric
acid;
4-(2-(15-Carboxypentadecanoylamino)phenoxy)butyramide;
4-(2-(14-Carboxytetradecanoylamino)phenoxy)butyric acid;
4-(2-(13-Carboxyl-tridecanoylamino)phenoxy)butyric acid;
4-(2-(12-Carboxy-dodecanoylamino)phenoxy)butyric acid;
4-(2-(11-Carboxy-undecanoylamino)phenoxy)butyric acid;
4-(2-(10-Carboxy-decanoylamino)phenoxy)butyric acid;
4-(2-(9-Carboxy-nonanoylamino)phenoxy)butyric acid;
4-(2-(8-Carboxyoctanoylamino)phenoxy)butyric acid;
4-(2-(7-Carboxyheptanoylamino)phenoxy)butyric acid;
4-(2-(6-Carboxyhexanoylamino)butyric acid;
4-(2-(20-Carboxyeicosanoylamino)phenylthio)butyric acid;
4-(2-(19-Carboxynonadecanoylamino)phenylthio)butyric acid;
4-(2-(18-Carboxyoctadecanoylamino)phenylthio)butyric acid;
4-(2-(17-Carboxyheptadecanoyl-N-ethylamino)phenylthio)butyric
acid;
4-(2-(16-Carboxyhexadecanoylamino)phenylthio)butyric acid;
4-(2-(15-Carboxypentadecanoylamino)phenylthio)butyric acid;
4-(2-(14-Carboxytetradecanoylamino)phenylthio)butyramide;
4-(2-(13-Carboxytridecanoylamino)phenylthio acid;
4-(2-(12-Carboxy-dodecanoylamino)phenylthio)butyric acid;
4-(2-(11-Carboxy-undecanoylamino)phenylthio)butyric acid;
4-(2-(10-Carboxydecanoylamino)phenylthio)butyric acid;
4-(2-(9-Carboxynonanoylamino)phenylthio)butyric acid;
4-(2-(8-Carboxyoctanoylamino)phenylthio)butyric acid;
4-(2-(7-Carboxyheptanoylamino)phenylthio)butyric acid;
4-(2-(6-Carboxyhexanoylamino)phenylthio)butyric acid;
3-(2-(16-Carboxyhexadecanoylamino)phenoxy)propionic acid;
4-(2-(15-Carboxyisohexadecanoylamino)phenoxy)butyric acid;
4-(2-(14-Carboxytetradecanoylamino)phenoxy)butyric acid;
5-(2-(13-Carboxytridecanoylamino)phenoxy)valeric acid;
5-(2-(12-Carboxydodecanoylamino)phenoxy)valeric acid;
5-(2-(11-Carboxyisododecanoylamino)valeric acid;
4-(2-(11-Carboxyundecanoylamino)isovaleric acid;
4-(2-(10-Carboxydecanoylamino)isovaleric acid;
5-(2-(9-Carboxynonanoylamino)phenoxy)valeric acid;
6-(2-(9-Carboxynpnanoylamino)phenoxy)caproic acid;
6-(2-(8-Carboxyoctanoylamino)phenoxy)caproic acid;
6-(2-(7-Carboxyisooctanoylamino)phenoxy)caproic acid;
7-(2-(7-Carboxyheptanoylamino)phenoxy)enanthic acid;
7-(2-(6-Carboxyhexanoylamino)phenoxy)enanthic acid;
7-(2-(5-Carboxyisohexanoylamino)phenoxy)enanthic acid;
2-(2-(12-Carboxydodecanoylamino)phenoxy)acetic acid;
2-(2-(11-Carboxyundecanoylamino)phenoxy)acetic acid;
2-(2-(10-Carboxydecanoylamino)phenoxy)acetic acid;
3-(2-(9-Carboxynonanoylamino)phenoxy)propionic acid;
3-(2-(12-Carboxydodecanoylamino)phenylthio)propionic acid;
3-(2-(11-Carboxyundecanoylamino)phenylthio)propionic acid;
3-(2-(11-Carboxyundecanoylamino)phenylthio)isobutyric acid;
4-(2-(19-Carboxynonadecanoyl-N-methylamino)phenylthio)butanesulfonic
acid;
4-(2-(18-Carboxyoctadecanoylamino)phenylthio)butanesulfonic
acid;
4-(2-(17-Carboxyheptadecanoylamino)phenylthio)butanesulfinic
acid;
4-(2-(16-Carboxyhexadecanoylamino)phenylthio)butanethiosulfonic
acid, sodium salt;
4-(2-(14-Carboxytetradecanoyl
N-propylamino)phenylthio)butanephosphonic acid;
4-(2-(13-Carboxytridecanoylamino)phenylthio)butanesulfonic
acid;
4-(2-(12-Carboxydodecanoylamino)phenylthio)butanesulfinic acid;
4-(2-(11-Carboxyundecanoylamino)phenylthio)butanethiosulfonic acid,
sodium salt;
4-(2-(9-Carboxynonanoylamino)phenylthio)butanephosphonic acid;
4-(2-(8-Carboxyoctanoylamino)phenylthio)butanesulfonic acid;
4-(2-(7-Carboxyheptanoylamino)phenylthio)butanesulfinic acid;
4-(2-(6-Carboxyhexanoylamino)phenylthio)butanethiosulfonic acid,
sodium salt;
3-(2-(15-Carboxyisohexadecanoylamino)phenoxy)isobutanephosphonic
acid;
3-(2-(14-Carboxytetradecanoylamino)phenoxy)isobutanoic acid;
5-(2-(13-Carboxytridecanoylamino)phenoxy)pentanesulfinic acid;
5-(2-(12-Phosphonododecanoylamino)phenoxy)valeramide;
5-(2-(11-Sulfoundecanoylamino)valeric acid;
5-(2-(10-Sulfinodecanoyl N-methylamino)phenoxy valeric acid;
5-(2-(9-Thiosulfatononanoylamino)phenoxy)valeric acid, sodium
salt;
6-(2-(9-Phosphonononanoylamino)phenoxy)caproic acid;
6-(2-(7-Sulfoisooctanoyl-N-methylamino)phenoxy)caproic acid;
7-(2-(7-Sulfinoheptanoyl-N-ethylamino)phenoxy)enanthic acid;
7-(2-(6-Thiosulfatohexanoylamino)phenoxy)enanthamide, sodium
salt
7-(2-(5-Phosphonoisohexanoylamino)phenoxy)enanthic acid;
2-(2-(11-Sulfoundecanoylamino)phenoxy)acetic acid;
2-(2-(10-Sulfodecanoyl-N-propylamino)phenoxy)acetic acid;
3-(2-(9-Sulfinononanoylamino)phenoxy)propionic acid;
3-(2-(12-Thiosulfatododecanoylamino)phenylthio)propionamide, sodium
salt;
3-(2-(11-Phosphonoundecanoylamino)phenylthio)propionic acid;
3-(2-(11-Sulfoundecanoylamino)-4-methyl-phenylthio)isobutyric
acid;
3-(2-(12-Sulfinododecanoylamino)phenylthio)isobutyramide;
5-(2-(11-Thiosulfoundecanoyl-N-butylamino)phenylthio)valeric acid,
sodium salt;
5-(2-(10-Phosphonodecanoylamino)phenylthio)valeric acid;
5-(2-(12-Phosphonododecanoylamino)phenylthio)pentane-sulfonic
acid;
5-(2-(11-Carboxydecanoylamino)phenylthio)pentane sulfinic acid;
5-(2-(10-Phosphonodecanoylamino)phenylthio)pentanethiosulfonic
acid;
6-(2-(12-Phosphonododecanoylamino)phenylthio)hexanephosphonic
acid;
4-(2-(11-Sulfinoundecanoylamino)4-methyl-phenoxy)butane-thiosulfonic
acid, sodium salt;
4-(2-(12-Sulfododecanoylamino)6-methylphenoxy)butane sulfonic
acid;
4-(2-(11-Sulfodecanoylamino)3-chloro)phenylthio)-butane-sulfinic
acid;
4-(2-(10-Sulfodecanoylamino)4-methylphenoxy)butanethiosulfonic
acid, sodium salt;
4-(2-(12-Sulfododecanoylamino)6-methylphenoxy)-butane-phosphonic
acid;
5-(2-(11-Sulfinoundecanoylamino)-3-methylphenylthio)pentane-sulfonic
acid;
4-(2-(11-Sulfinoundecanoylamino)-3-methylsulfonylphenoxy)butane-sulfinic
acid;
4-(2-(11-Sulfinoundecanoylamino)-4-methylsulfonyl)-phenylthio)butanesulfoni
c acid;
4-(2-(12-Sulfinododecanoylamino)5-ethyl-phenoxy)-butane-phosphonic
acid;
4-(2-(10-Sulfinodecanoylamino)-3,5-dimethylphenoxy)-butane-sulfonic
acid;
4-(2-(9-Thiosulfatononanoylamino)-4-fluoro-phenoxy)butane-sulfinic
acid, sodium salt;
4-(2-(12-Thiosulfatododecanoylamino)-5-trifluromethylphenoxy)butane-thiosul
fonic acid, sodium salt;
4-(2-(10-Thiosulfatodecanoylamino)-4-hydroxyphenylthio)butane-phosphbnic
acid, sodium salt;
4-(2-(9-Phosphonononanoylamino)-3,5-dimethoxyphenylthio)butyric
acid;
5-(2-(11-Sulfoundecanoylamino)-4-nitrophenoxy)-valeric acid;
4-(2-(11-Sulfinoundecanoylamino)-5-amino-3-methylphenoxy)butyric
acid;
4-(2-(11-Thiosulfatoundecanoylamino)-5-amino-4-methylphenylthio)butyric
acid, sodium salt;
4-(2-(12-Phosphonododecanoylamino)-4-dimethyl-aminophenoxy)butyric
acid;
4-(2-(10-Sulfodecanoylamino)-phenoxy)butyric acid;
3-(2-(9-Sulfinononanoylamino)phenoxy)propionic acid;
3-(2-(12-Thiosulfatododecanoylamino)phenoxy)-3-methylpropionic
acid, sodium salt;
3-(2-(11-Phosphonodecanoylamino)thienyloxy)-2-chloropropionic
acid;
4-(2-(9-Sulfononanoylamino)thienyloxy-3-ethoxybutyric acid;
4-(2-(12-Sulfinododecanoylamino)phenoxy)-2-fluorobutyric acid;
7-(2-(11-Thiosulfatoundecanoylamino)phenoxy)6-aminoenanthic acid,
sodium salt;
5-(2-(11-Phosphonoundecanoylamino)-3-methylphenoxy)-4-oxo-valeric
acid;
4-(2-(12-Sulfododecanoylamino)phenoxy)but-2-enoic acid;
4-(2-(11-Sulfinodecanoylamino)phenoxy)but-2-enoic acid;
4-(2-(10-Thiosulfatodecanoylamino)phenoxy)-4-methylene valeric
acid, sodium salt;
4-(2-(9-Phosphonononanoylamino)phenoxy)-4-fluoro-2-butenoic
acid;
4-(2-(11-Sulfo-3-methylbutanoylamino)thienyloxy)-butyric acid;
4-(2-(4-Sulfino-3-chlorobutanoylamino)thienyloxy)-butyric acid;
4-(2-(9-Thiosulfato-2-methoxynonanoylamino)thienyloxy)butyric acid,
sodium salt;
4-(2-(4-Phosphono-2-ethoxybutanoylamino)phenoxy)butyric acid;
4-(2-(14-Sulfo-14-fluoro-2-acetamidotetradecanoylamino)-3-methylphenoxy)but
yric acid;
4-(2-13-Sulfino-2-oxotridecanoylamino)-4-methylthio)-phenyloxy)butyric
acid;
4-(2-(12-Thiosulfatododecanoyl-3-en-amino)phenoxy)butyric acid;
4-(2-(11-Phosphonoundecanoyl-7-ene-amino)phenoxy)butyric acid;
4-(2-(4-Sulfo-2-fluoro-2-butenoylamino)phenoxy)-butyric acid;
4-(2-(12-Sulfinododecanoylamino)-4-methyl-3-pyridyloxy)butyric
acid;
4-(2-(11-Thiosulfatoundecanoylamino)-4-methyl-3-pyridyloxy)butyric
acid;
4-(2-(10-Phosphonodecanoylamino)-5-methyl-3-pyridyloxy)butyric
acid;
4-(2-(11-Sulfinodecanoylamino)-4-nitro-3-pyridylthiobutyric
acid;
4-(2-(10-Thiosulfatodecanoylamino)-6-methylsulfonyl-3-pyridyloxy)butyric
acid, sodium salt;
4-(2-(9-Phosphonononanoylamino)5-chloro-3-pyridylthio)butyric
acid;
4-(2-(11-Sulfoundecanoylamino)5-methylsulfonyl-3-pyridylthio)butyric
acid;
4-(2-(11-Sulfinoundecanoylamino)-6-methyl-3-pyridylthio)butyric
acid;
4-(2-(11-Thiosulfatoundecanoylamino)-4,6-dimethyl-3-pyridyloxy)butyric
acid, sodium salt;
4-(2-(12-Phosphonododecanoylamino)-5-(methylthio)-3-pyridyloxy)butyric
acid;
4-(2-(10-Sulfodecanoylamino)-5-methoxy-3-pyridyloxy)butyric
acid;
4-(2-(9-Sulfinononanoylamino)-4-fluoro-6-methyl-3-pyridyloxy)butyric
acid;
4-(2-(12-Thiosulfatododecanoylamino)5-(methylamino)-3-pyridyloxy)butyric
acid, sodium salt;
4-(2-(11-Phosphonoundecanoylamino)4-phenyl-3-pyridylthio)butyric
acid;
4-(2-(9-Sulfounonanoylamino)6-methoxy-3-pyridylthio)butyric
acid;
4-(2-(12-Sulfinododecanoylamino)-6-trifluoromethyl-3-pyridyloxy)butyric
acid;
5-(2-(11-Thiosulfatoundecanoylamino)-4-methyl-3-thiophenyloxy)valeric
acid, sodium salt;
4-(2-(11-Phosphonoundecanoylamino)-4-methyl-3-thiophenyloxy)butyric
acid;
4-(2-(12-Sulfododecanoylamino)-5-methyl-3-thiophenylthio)butyric
acid;
4-2(-(11-Sulfinoundecanoylamino)-4-methyl-3-thiophenylthio)butyric
acid;
4-(2-(10-Thiosulfatodecanoylamino)-5-methyl-3-thienylthio)butyric
acid, sodium salt;
4-(2-(9-Phosphonononanoylamino)-4-hydroxy-3-thienyloxy)butyric
acid:
4-(2-(11-Sulfodecanoylamino)-4-methylthio-3-thienyloxy)butyric
acid;
4-(2-(10-Sulfinodecanoylamino)-4-methylsulfonyl-3-thienyloxy)butyric
acid;
4-(2-(9-Thiosulfatononanoylamino)-4-methylsulfonyl-3-thienyloxy)butryic
acid, sodium salt;
4-(2-(12-Phosphonododecanoylamino)-5-trifluoromethyl-3-thienyloxy)butyric
acid;
4-(2-(11-Sulfoundecanoylamino)-4-methyl-5-phenyl-3-thienyloxy)butyric
acid;
4-(2-(11-Sulfinoundecanoylamino)-5-methylamino-3-thienyloxy)butyric
acid;
4-(2-(12-Thiosulfatododecanoylamino)-5-dimethylamino-3-thienyloxy)butyric
acid, sodium salt;
4-(2-(11-Phosphonoundecanoylamino)-4-amino-3-thienyloxy)butyric
acid;
Preferred compounds in the invention include:
4-(2-(11-Carboxyundecanoylamino)phenoxy)butyric acid,
4-(2-(11-Carboxyundecanoylamino)phenylthio)butyric acid,
4-(2-(9-Carboxynonanoylamino)phenoxy)butyric acid,
4-(2-(10-Carboxydecanoylamino)phenoxy)butyric acid,
4-(2-(12-Carboxydodecanoylamino)phenoxy)butyric acid,
4-(2-(13-Carboxytridecanoylamino)phenoxy)butyric acid,
4-(2-(15-Carboxypentadecanoylamino)phenoxy)butyric acid,
4-(2-(11-Carboxyundecanoylamino)-4-methylphenoxy)-butyric acid,
4-(2-(11-Carboxyundecanoylamino)-5-methylphenoxy)-butyric acid.
Also included as a 5.alpha.-reductase inhibitor in this invention
is an agent of the following formula: ##STR51## wherein A is an
1,2-disubstituted aromatic ring, preferably a benzene ring;
D is OH, NH.sub.2, NHR.sub.c, OR.sub.c ;
X is O, S, SO, or SO.sub.2 ;
R is H,
C.sub.1 -C.sub.4 alkyl,
phenyl or substituted phenyl,
halo,
haloalkyl,
hydroxy,
carboxy,
cyano,
C.sub.1 -C.sub.4 alkoxy,
C.sub.1 -C.sub.4 alkylthio,
C.sub.1 -C.sub.4 alkylsulfinyl,
C.sub.1 -C.sub.4 alkylsulfonyl,
nitro,
amino,
C.sub.1 -C.sub.4 mono or di-alkylamino;
R' and R" are independently
H,
halo,
C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy,
amino, or oxo, where CH--R' or CH--R" in the formula become
--C.dbd.O;
R.sub.a is H, C.sub.1 -C.sub.4 alkyl;
R.sub.b, R.sub.c are independently, C.sub.1 -C.sub.12 alkyl,
phenyl,
phenyl-C.sub.1 -C.sub.4 alkyl;
n is 0-2;
y is 1-6;
z is 6-20; and
wherein ##STR52## can independently represent substituted or
unsubstituted alkyl radicals or alkenyl radicals containing at
least one alkene bond;
and pharmaceutically acceptable salts and esters thereof.
The compounds of the instant invention are inhibitors of the human
testosterone 5.alpha.-reductase.
The scope of the compounds of the instant invention are described
by the above-described formula.
In the description of the formula the following terms are used
which are hereby defined:
X can be O or S, preferably one X being O, and particularly
preferred wherein both Xs are O, i.e., the catechol structure.
"C.sub.1 -C.sub.4 alkyl" includes linear or branched species, e.g.
methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl,
sec-butyl, t-butyl; and "C.sub.1 -C.sub.12 alkyl" includes alkyl up
to 12 carbons including n-octyl, t-decyl, n-dodecyl.
"Phenyl C1-C4 alkyl" includes benzyl, 2-phenethyl, and the
like;
"C.sub.1 -C.sub.4 alkoxy" includes linear or branched species,
e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,
sec-butoxy, t-butoxy;
"Halo" includes fluoro, chloro, bromo or iodo;
"Substituted phenyl" includes phenyl substituted by one or more of
C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, or halo, and the
like, as defined above; representative examples include o, m-,
p-methoxy phenyl; 2,4-dimethoxyphenyl; 2-chloro-4-ethoxyphenyl;
3,5-dimethoxyphenyl; 2,4-dichlorophenyl; 2-bromo-4-methylphenyl,
o-fluorophenyl, and the like.
"Haloalkyl" includes C.sub.1 -C.sub.4 alkyl, defined above,
substituted with one or more "halo" as defined above and includes:
trifluoromethyl, 2,2-dichloroethyl and the like.
"C.sub.1 -C.sub.4 alkylthio" includes C.sub.1 -C.sub.4 alkyl,
defined above, substituted with at least one divalent thio (--S--)
grouping including; methylthio, ethylthio, isopropylthio,
n-butylthio, and the like.
"C.sub.1 -C.sub.4 alkylsulfinyl" includes C.sub.1 -C.sub.4 alkyl,
defined above, substituted with at least one --SO-- grouping
including; methylsulfinyl, ethylsulfinyl; isopropylsulfinyl, and
the like.
"C.sub.1 -C.sub.4 alkylsulfonyl" includes C.sub.1 -C.sub.4 alkyl,
defined above, substituted with at least one sulfonyl group,
--SO.sub.2 --, including; methylsulfonyl, ethylsulfonyl,
isopropylsulfonyl, n-butylsulfonyl, and the like;
"C.sub.1 -C.sub.4 mono or dialkyl amino" includes amino,
substituted with one or more C.sub.1 -C.sub.4 alkyl groups as
defined hereinabove, including: methylamino, ethylamino,
n-butylamino, t-butylamino, dimethylamino, N,N-diethylamino,
methyl-t-butylamino, and the like.
The R group or groups on the benzene ring can be present initially
in the process, e.g. phenyl, methyl, methoxy, cyano, carbomethoxy,
trifluoromethyl, (present as in the starting 6-nitrophenol 1 in
Flow Chart A) or added later by a conventional reaction, e.g.
chloro, as by chlorination, nitro by nitration, or created from a
starting or added functional group present, e.g. converting a later
added nitro to an amino group by catalytic reduction, then
alkylating to a mono or dialkylamine. An amino group can be
subjected to diazotization to a hydroxy group, which can be
followed by methylation to a methoxy group. Similarly, a hydroxy
group can be converted to a thiol by the analogous procedures
described in J. Org. Chem. 31, pp 3980-3984 (1966) by Newman and
Karnes, and J. Org. Chem. 31, pp 410 (1966) by Kwart, H. and Evans,
E. S. The resulting thiol can be alkylated to alkylthio, which can
be oxidized to the corresponding sulfoxide or sulfone. Preferred
substituents are H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy
and phenyl. These reactions and sequences are conventional in the
art and it will be obvious to one skilled in the art to modify the
benzene ring to arrive at an R radical disclosed herein.
By the term "pharmaceutically acceptable salts and esters thereof"
is meant salts and esters of the acid groups in the final molecule
which can be used as part of the human drug delivery system and
include the salts: sodium, potassium, calcium, ammonium,
substituted Ammonium, quaternary ammonium, and esters: ethyl ester,
aceturate, besylate, edetate, phenpropionate, acetate, pamoate, and
esters which serve as "prodrug" formulations which will hydrolyze
in the body at physiological pH's to regenerate the acid, including
pivaloylates, e.g. pivoxetil and pivoxil, and Kanebo esters, and
the like. ##STR53## where y is 1-6, preferably 3, can contain at
least one R' substituent as defined above, and can be, e.g.,
##STR54## and the like.
An alkene bond can also be present in ##STR55## e.g., CH.sub.2
--CH.dbd.CH--; CH.sub.2 --CH.dbd.CH--CH.sub.2 --; --CH.sub.2
--CH.dbd.CH--; --(CH.sub.2).sub.3 --CH.dbd.CH-- and the like.
##STR56## where z is 6-20, preferably 8-14, can contain at least
one R" substituent as defined above, and can be completely alkyl;
e.g., (CH.sub.2)n-COOH, where n is 8-14 preferably and the
like.
An alkene bond can also be present in ##STR57## e.g.,
--(CH.sub.2).sub.4 --CH.dbd.CH--(CH.sub.2).sub.4 --, and the
like.
Preferred is where one R' or R" is H and particularly preferred is
where both ##STR58## are alkyl.
Preferred compounds of the instant invention are given by the
following formulas; ##STR59## wherein R, R', R", Y, Z, R.sub.b are
defined above; and particularly preferred are: ##STR60## where n is
8-14, and R.sub.b is methyl, ethyl, cyclopropyl, isopropyl,
n-propyl, t-butyl, phenyl or benzyl.
The compounds of the instant invention can be made by the
procedures outlined in the following Flowcharts. ##STR61##
As seen in Flow Chart A-3, o-nitrophenol 1, ethyl 4-bromobutyrate 2
and anhydrous K.sub.2 CO.sub.3 in e.g., dry acetone are heated at
reflux e.g. for 12-100 hours, or stirred for an extended period of
time at room temperature, under a nitrogen atmosphere to product
ethyl 4-(2-nitrophenoxy) butyrate 3, in Step (A).
A solution of 3 in e.g., ethyl acetate is catalytically
hydrogenated at room temperature under e.g. 40 psig of H.sub.2 in
the presence of a 5% Pd/C catalyst to yield ethyl
4-(2-aminophenoxy)butyrate 4 in Step (B).
Step (C) comprises reacting the 12-bromo dodecanoic acid 5 with
isopropyl mercaptan in a suitable solvent, e.g., dimethoxyethane,
at about 80-85.degree. C. to obtain the acid 6.
In Step (D) the mono acid 6 is reacted with the amine 4 and
N'N'-dicyclohexylcarbodiimide (DCC) at e.g., room temperature in
e.g., dry methylene chloride, optionally in the presence of
4-dimethylaminopyridine, to produce the amide 7.
In Step (E), the ether-amide 7 is de-esterified by e.g., 2.5 N NaOH
in MeOH/H.sub.2 O to yield the final product, monoacid 8.
The monoacid 8 can be treated with NaIO.sub.4 in (acetone/water) at
room temperature for (4-24 hours) to produce the corresponding
sulfoxide 8a. Additionally, 8 can be treated with
meta-chlorobenzoic acid in (CH.sub.2 Cl.sub.2) at a temperature of
about 0.degree. to 25.degree. C. for (1-24 hours) to produce the
corresponding sulfone 8b.
In Step (F) the ester 7 is treated with ammonia in (methanol) at
room temperature for, e.g., 1-7 days to produce the amide 9.
Flow Chart B-3 illustrates the synthesis of the sulfur analogs of
the invention compounds.
In Step G, the orthoaminothiophenol is reacted with the bromoester
2 under conditions similar to Step A to produce the thioether
11.
In Step (H), the thiother 11 is reacted with an alkylthioalkanoic
acid under similar conditions using DCC analogously as in Step D to
produce the acylated ester 12.
In Step I, the ester 12 is hydrolyzed to produce the free thio acid
13, which has the 5-.alpha.-reductase activity described
herein.
As seen in Flow Chart C-3, the compound 13 can further be oxidized
to the sulfoxide in Step J.sub.a, starting with the thio compound
14 to produce the sulfoxide 15, which can be hydrolyzed, analogous
to the conditions in Step I to produce the active acid 16.
In a similar manner, 14 can be converted to the sulfone-ester 17,
which can then be hydrolyzed analogous to the conditions in Step I
to the corresponding acid 18.
Alternatively, the sulfur in o-nitrobenzene thiol as a separate
starting material analogous to 1, can be coupled to yield the ester
alkylthio compound corresponding to 3 which can be oxidized to the
corresponding sulfoxide or sulfone, then followed by reduction of
the nitro group to the amino and then coupled with a suitable
reagent e.g., 6, to yield the linear amide containing unoxidized
sulfur analogous to 7. A further modification is where the
sulfuracylating agent is first oxidized to the corresponding
sulfoxide or sulfone, then coupled with the amino group of e.g., 11
to yield e.g. 13 containing only an oxidized sulfur in the amide
chain.
It is obvious that other nitrophenols can be substituted for 1 in
Flow Chart A-3 to provide the scope of the compounds covered by
this invention and include the following:
2-nitrophenol
2-nitro-6-methylphenol
2-nitro-5-methylphenol
2-nitro-4-methylphenol
2-nitro-3-methylphenol
2-nitro-4-phenylphenol
2-nitro-5-phenylphenol
2-nitro-4-chlorophenol
2-nitro-4-(trifluoromethyl)phenol
2-nitro-4-methoxyphenol
2-nitro-6-ethoxyphenol, and the like.
Starting materials for Flow Charts B-3 and C-3 in addition to 10
are commercially available and readily made by prior art procedures
and include all of the above listed compounds where --SH is
substituted for --OH, ortho to the nitro group.
Other starting materials for 2 in both Flow Charts A-3 and B-3
include the following:
Br--CH.sub.2 --COOMe,
Cl--CH.sub.2 CH.sub.2 CH.sub.2 COOCH(CH.sub.3).sub.3,
Br--CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 COOMe,
Br--CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 COOEt,
Br--CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2
COOCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3,
Br--CH.sub.2 CH(CH.sub.3)COOMe,
Br--CH.sub.2 CH(CH.sub.3)CH.sub.2 COOEt,
Br--CH.sub.2 CH.sub.2 CH.sub.2 COOMe,
Br--CH.sub.2 CH(OCH.sub.3)CH.sub.2 COOCH(CH.sub.3).sub.2,
Cl--CH.sub.2 CH(OCH.sub.2 CH.sub.3)CH.sub.2 COOMe,
Br--CH.sub.2 CH(F)CH.sub.2 COOMe,
and the like.
Other starting materials for the acid 6 to produce the acid for
acylating the amino group in 4 or 11 include the following:
MeS--(CH.sub.2).sub.6 COOH,
MeS--(CH.sub.2).sub.7 COOH,
(CH.sub.3).sub.2 CHS--(CH.sub.2).sub.8 COOH,
EtS--(CH.sub.2).sub.9 COOH,
CH.sub.3 CH.sub.2 CH.sub.2 S(CH.sub.2).sub.10 COOH,
(CH.sub.3).sub.2 CHS(CH.sub.2).sub.11 COOH,
MeS--(CH.sub.2).sub.12 COOH,
EtS--(CH.sub.2).sub.13 COOH,
CH.sub.3 CH.sub.2 CH.sub.2 S--(CH.sub.2).sub.14 COOH,
(CH.sub.3).sub.2 CHS--(CH.sub.2).sub.15 COOH,
CH.sub.3 (CH.sub.2).sub.3 S--(CH.sub.2).sub.16 COOH,
(CH.sub.3).sub.2 CH--CH.sub.2 S--(CH.sub.2).sub.17 COOH,
CH.sub.3 --CH.sub.2 --CH.sub.2 --S--(CH.sub.2).sub.18 COOH,
(CH.sub.3).sub.2 CHS--(CH.sub.2).sub.19 COOH,
EtS--(CH.sub.2).sub.20 COOH,
MeS--CH(CH.sub.3)--(CH.sub.2).sub.10 COOH,
(CH.sub.3).sub.2 CHS--CH.sub.2 CH.sub.2 CH(CH.sub.3)CH.sub.2 COOH,
##STR62## EtS--CH.sub.2 CH(OCH.sub.3)(CH.sub.2).sub.7 COOH,
CH.sub.3 CH.sub.2 CH.sub.2 S--CH.sub.2 CH(OCH.sub.2
CH.sub.3)CH.sub.2 CH.sub.2 COOH,
CH.sub.3 (CH.sub.2).sub.7 --S--CH.sub.2 --COOH
(CH.sub.3).sub.2 CH(CH.sub.2).sub.5 --S--CH.sub.2 --COOH
CH.sub.3 (CH.sub.2).sub.9 --S--CH.sub.2 --COOH
CH.sub.3 (CH.sub.2).sub.11 S--CH.sub.2 COOH, and the like.
Representative compounds of the instant invention include, but are
not limited to:
4-(2-(20-Isopropylthioeicosanoylamino)phenoxy)butyric acid;
4-(2-(19-Methylthiononadecanoylamino)phenoxy)butyric acid;
4-(2-(18-Ethylthioloctadecanoylamino)phenoxy)butyric acid;
4-(2-(17-Isopropylthioheptadecanoylamino)phenoxy)-butyric acid;
4-(2-(16-Methylthiohexadecanoylamino)phenoxy)butyric acid;
4-(2-(15-Methylsulfinylpentadecanoylamino)phenoxy)-butyric
acid;
4-(2-(14-Methylsulfinyltetradecanoylamino)phenoxy)-butyric
acid;
4-(2-(13-n-Propylthiotridecanoylamino)phenoxy)-butyric acid;
4-(2-(12-n-Butylsulfinyldodecanoylamino)phenoxy)-butyric acid;
4-(2-(11-sec-Butylthioundecanoylamino)phenoxy)-butyric acid;
4-(2-(10-phenylthiodecanoylamino)phenoxy)-butyric acid;
4-(2-(10-benzylthiodecanoylamino)phenoxy)-butyric acid;
4-(2-(10-iso-Butylsulfonyldecanoylamino)phenoxy)-butyric acid;
4-(2-(9-t-Butylthiononanoylamino)phenoxy)butyric acid;
4-(2-(8-Ethylsulfonyloctanoamino)phenoxy)butyric acid;
4-(2-(7-Isopropylthioheptanoylamino)phenoxy)butyric acid;
4-(2-(6-Methylthiohexanoylamino)butyric acid;
4-(2-(20-Ethylsulfonyleicosanoylamino)phenylthio)-butyric acid;
4-(2-(19-Isopropylthiononadecanoylamino)phenylthio)-butyric
acid;
4-(2-(18-Methylthiooctadecanoylamino)phenylthio)-butyric acid;
4-(2-(17-Ethylthioheptadecanoylamino)phenylthio)-butyric acid;
4-(2-(16-Isopropylhexadecanoylamino)phenylthio)-butyric acid;
4-(2-(15-Methylthiopentadecanoylamino)phenylthio)-butyric acid;
4-(2-(14-Methylsulfinyltetradecanoylamino)phenylthio-butyric
acid;
4-(2-(13-Methylsulfonyltridecanoylamino)butyric acid;
4-(2-(12-n-Propylthiododecanoylamino)phenylthio)-butyric acid;
4-(2-(11-n-Butylsulfinylundecanoylamino)phenylthio)-butyric
acid;
4-(2-(10-sec-Butylthiodecanoylamino)phenylthio)-butyric acid;
4-(2-(10-phenylthiodecanoylamino)phenylthio)-butyric acid;
4-(2-(10-benzylthiodecanoyiamino)phenylthio)-butyric acid;
4-(2-(9-iso-Butylsulfonylnonanoylamino)phenylthio)-butyric
acid;
4-(2-(8-t-Butylthiooctanoylamino)phenylthio)butyric acid;
4-(2-(7-Ethylsulfinylheptanoylamino)phenylthio butyric acid;
4-(2-(6-Isopropylthiohexanoylamino)phenylthio butyric acid;
3-(2-(16-Methylsulfinylhexadecanoylamino)phenoxy)-propionic
acid;
4-(2-(15-Methylsulfonylisohexadecanoylamino)phenoxy)-butyric
acid;
3-(2-(14-n-Propylthiotetradecanoylamino)phenoxy)-isobutyric
acid;
5-(2-(13-n-Butylsulfinyltridecanoylamino)phenoxy)-valeric acid;
5-(2-(12-sec-Butylthiododecanoylamino)phenoxy)-valeric acid;
5-(2-(11-iso-Butylsulfonylisododecanoylamino)-valeric acid;
5-(2-(11-t-Butylthioundecanoylamino)valeric acid;
5-(2-(10-Ethylsulfinyldecanoylamino)valeric acid;
5-(2-(9-Isopropylthiononanoylamino)phenoxy)valeric acid;
6-(2-(9-Methylthiononanoylamino)phenoxy)caproic acid;
6-(2-(8-Ethylthiooctanoylamino)phenoxy)caproic acid;
6-(2-(7-Isopropylthioisooctanoylamino)phenoxy)caproic acid;
7-(2-(7-Methylheptanoylamino)phenoxy)enanthic acid;
7-(2-(6-Methylsulfinylhexanoylamino)phenoxy)enanthic acid;
7-(2-(5-Methylsulfonylisohexanoylamino)phenoxy)-enanthic acid;
2-(2-(12-n-Propylthiododecanoylamino)phenoxy))acetic acid;
2-(2-(11-n-Butylsulfinylundecanoylamino)phenoxy)acetic acid;
2-(2-(10-sec-Butylthiodecanoylamino)phenoxy)acetic acid;
3-(2-(9-iso-Butylsulfonylnonanoylamino)propionic acid;
3-(2-(12-t-Butylthiododecanoylamino)phenylthio)-propionic acid;
3-(2-(11-Ethylsulfinylundecanoylamino)phenylthio)-propionic
acid;
4-(2-(11-Isopropylthioundecanoylamino)phenylthio)-butyric acid;
4-(2-(11-Methylthioundecanoylamino)-4-methyl-thiophenoxy)butyric
acid;
4-(2-(12-Ethylthiododecanoylamino)phenylthio)-butyric acid;
5-(2-(11-Isopropylthioundecanoylamino)phenylthio)-valeric acid;
5-(2-(10-Methylthiodecanoylamino)phenylthio)valeric acid;
5-(2-(9-Methylsulfinylnonanoylamino)phenylthio)-valeric acid;
5-(2-(12-Methylsulfonyldodecanoylamino)phenylthio)-valeric
acid;
5-(2-(11-n-Propylthiodecanoylamino)phenylthio)-valeric acid;
5-(2-(10-n-Butylsulfinyldecanoylamino)phenylthio)-valeric acid;
6-(2-(9-sec-Butylthiononanoylamino)phenoxy)caproic acid;
6-(2-(12-iso-Butylsulfonyldodecanoylamino)phenylthio)caproic
acid;
6-(2-(11-t-Butylthioundecanoylamino)phenylthio)-caproic acid;
7-(2-(11-Ethylsulfinylundecanoylamino)-3-methylphenyl-thio)enanthic
acid;
7-(2-(11-Isopropylthioundecanoylamino)-4-methylphenyl-thio)enanthic
acid;
7-(2-(12-Methylthiododecanoylamino)phenoxy)enanthic acid;
4-(2-(11-Phenylthioundecanoylamino)4-methyl-phenoxy)-butyric
acid;
4-(2-(10-Benzylthiodecanoylamino)3-methylphenoxy)-butyric acid;
4-(2-(9-Methylthiononanoylamino)5-methylphenoxy)-butyric acid;
4-(2-(12-Methylsulfinyldodecanoylamino)6-methyl-phenoxy)butyric
acid;
4-(2-(11-Methylsulfonyldecanoylamino)3-phenylthio)butyric acid;
4-(2-(10-n-Propylthiodecanoylamino)4-methylphenoxy)-butyric
acid;
4-(2-(9-n-Butylsulfinylnonanoylamino)5-fluoromethylphenylthio)butyric
acid;
4-(2-(12-sec-Butylthiododecanoylamino)6-methylphenoxy)butyric
acid;
5-(2-(11-iso-Butylsulfonylundecanoylamino)-3-methylphenylthio)valeric
acid;
4-(2-(11-t-Butylthioundecanoylamino)-3-methylsulfonylphenoxy)butyric
acid;
4-(2-(11-Ethylsulfinylundecanoylamino)-4-methylsulfonylphenylthio)butyric
acid;
4-(2-(12-Isopropylthiododecanoylamino)5-ethylphenoxy)butyric
acid;
4-(2-(11-Methylthioundecanoylamino)4-phenylphenoxy)-butyric
acid;
4-(2-(10-Ethylthiodecanoylamino)-3,5-dimethylphenoxy)-butyric
acid;
4-(2-(9-Isopropylthiononanoylamino)-4-fluoro-phenoxy)-butyric
acid;
4-(2-(12-Methylthiododecanoylamino)-5-trifluoromethylphenoxy)butyric
acid;
4-(2-(11-Isopropylthio)undecanoylamino)phenoxy)butyric acid,
4-(2-(11-Ethylthio)undecanoylamino)phenylthio)butyric acid,
4-(2-(9-Isopropylthio)nonanoylamino)phenoxy)butyric acid,
4-(2-(10-Isopropylthio)decanoylamino)phenoxy)butyric acid,
4-(2-(12-Isopropylthio)dodecanoylamino)phenoxy)butyric acid,
4-(2-(13-Butylthio)tridecanoylamino)phenoxy)butyric acid,
4-(2-(15-t-Butylthio)pentadecanoylamino)phenoxy)butyric acid,
5-(2-(11-Isopropylthio)undecanoylamino)phenoxy)valeric acid,
4-(2-(11-Ethylsulfinyl)undecanoylamino)-phenoxy)butyric acid,
4-(2-(11-Isopropylsulfonyl)undecanoylamino)-4-methylphenoxy)butyric
acid,
4-(2-(11-Ethylsulfinyl)undecanoylamino)-5-methylphenoxy)butyric
acid.
All of the compounds described above in the present invention,
prepared in accordance with the methods described above, are, as
already described, can be used to treat prostatic cancer in
combination with an antiandrogen, i.e. flutamide, by oral,
parenteral or topical administration.
In this invention, the antiandrogen, and the 5.alpha.-reductase
inhibitor are administered in combination as separate or one single
combined pharmaceutical composition via parenteral or oral means.
Preferably the antiandrogen and the 5.alpha.-reductase inhibitor
are administered orally as separate compositions.
The amount of each component administered is determined by the
attending clinicians taking into consideration the etiology and
severity of the disease, the patient's condition and age, the
potency of each component and other factors.
The antiandrogen compositions are generally administered in a
dosage range of about 0.20 to 40 mg/kg (body weight) per day with
250 to 750 mg per day, in equally divided doses, three (3) being
preferred.
The 5.alpha.-reductase inhibitor compositions are generally
administered in a dosage range of about 0.01 to 1.0 mglkg (body
weight) per day with one to 70 mg per day in one daily dose being
preferred.
In the preferred aspect of this invention, the antiandrogen is
4'-nitro-3'-trifluoromethylisobutyranilide, i.e. flutamide, which
is administered orally in a daily dose of about 750 mg/kg; the
5.alpha.-reductase inhibitor is finasteride, which is administered
orally in a daily dose of about 10 mg/kg.
The antiandrogen and the 5.alpha.-reductase inhibitor may be
compounded into a single dosage form suitable for oral or
parenteral administration. A tablet or capsule or caplets are
particularly convenient forms for oral administration. Such
compositions useful in the present invention are typically
formulated with conventional pharmaceutical excipients, e.g., spray
dried lactose and magnesium stearate into tablets or capsules for
oral administration. One or more of the active substances, with or
without additional types of active agents, can be worked into
tablets or dragee cores by being mixed with solid, pulverulent
carrier substances, such as sodium citrate, calcium carbonate or
dicalcium phosphate, and binders such as polyvinyl pyrrolidone,
gelatin or cellulose derivatives, possibly by adding also
lubricants such a magnesium stearate, sodium lauryl sulfate,
"Carbowax" or polyethylene glycols. Of course, taste improving
substances can be added in the case of oral administration
forms.
As further forms of administration, one can use plug capsules, e.g.
hard gelatin, as well as closed softgelatin capsules comprising a
softener or plasticizer, e.g. glycerine. The plug capsules contain
the active substance preferably in the form of a granulate, e.g.,
in mixtures with fillers, such as lactose, saccharose, mannitol,
starches such as potato starch or amylopectin, cellulose
derivatives or highly-dispersed silicic acids. In softgelatin
capsules, the active substance is preferably dissolved or suspended
in suitable liquids, such as vegetable oils or liquid polyethylene
glycols.
The active ingredient components used in accordance with the
present invention may also be formulated into once-a-day or even
longer sustained release composition by conventional techniques
well known in the art.
In place of oral administration, the active compounds may be
administered parenterally. In such case, one can use a solution of
the active substance, e.g., in sesame oil or olive oil.
The compositions when administered separately can be contained in a
suitable "kit" housing both pharmaceutical compositions in
clearly-marked sections and indicating dosage regimens. The kit can
be made of conventional materials.
Following the above treatment using the described regimen, prostate
cancer can be significantly inhibited, and in some cases reversed
into remission, when treating such androgen-dependent diseases in
accordance with this invention.
To assist in determining the effect of the prostatic cancer
treatment, blood plasma concentrations of testosterone (T),
dihydrotestosterone (DHT), and prostate acid phosphatase (PAP) as
well as prostate volume are measured. Lowered concentrations of DHT
and prostatic PAP, and reduction in prostate volume, are indicative
of successful treatment. The concentrations of the above-listed
components in plasma can be measured by standard methods well known
to those skilled in the art. (See, for example, R. Neri and M.
Monahan, Invest. Urology (1972), 10, 123-130 for prostatic AP
staining and E. Nieschlay and D. L. Loriaux, Z. Klin Chem. Klin
Biochem (1972), 4, 164 for radioimmunoassay determinations of
T.
The prostate volume is measured by rectal examination and/or by
transrectal ultrasonography. Objective assessment of the effect of
treatment is also measured by physical methods well known to these
skilled in the art of nuclear magnetic resonance imaging, as well
as by physical examination.
Further, and more desirably the effect of the combination therapy
can be quantified and evaluated by measuring the changes in serum
concentrations of prostate specific antigen (PSA). This is a 35K
dalton glycoprotein antigen, associated only with prostatic tissue,
discovered by Wang in 1979. (See Invest Urol, Vol. 17, p. 159
(1979.) Since that discovery, described in Supplement to Biology,
Vol. 37, No. 5, pp. 11-16 (May 1989) the clinical importance of
this new tumor marker has been recognized and is now widely
accepted as representing a significantly more effective and
reliable tumor marker than prostatic acid phosphatase (PAP).
Protocols for the clinical use of PSA marker in screening tests for
prostate cancer to determine staging and to monitor response to
therapy are published in the art. (See Journal of Urology, Vol.
142, pp. 1011-1017 (October 1989) by M. A. Hudson, et al.)
Using a protocol similar to that described in the above Hudson
paper, in which PSA was monitored, clinical trials on the effect of
finasteride were conducted. This study is the first clinical trial
to evaluate its efficacy in prostate cancer. Twenty-eight
hormone-naive patients with stage D prostate cancer were randomized
in a double-blinded fashion to receive MK-906 (10 mg/day) or
placebo. Patients were evaluated at 3 week intervals by rectal
examination and serum PSA, and at 6 week intervals by bone scan and
transrectal ultrasound. Patients were discontinued at the
investigators discretion when PSA levels increased from baseline.
After 12 weeks patient on placebo were switched to finasteride.
Thirteen patients received MK-906 and 15 patients received placebo.
A statistically significant decrease in the median percentage
change from baseline in PSA at weeks 3 and 6 occurred in the MK-906
group compared to the placebo group (-22.9% vs. -2.9%, and -15.1%
vs. +9.9%, respectively). Patients who remained on continuous
therapy for 24 weeks had 35-40% suppression in PSA. Serum
testosterone was not affected while dihydrosterosterone was
markedly lowered by MK-906 to castrate levels. Three patients in
each treatment group progressed on bone scan while none
demonstrated regression.
In summary, a decrease in serum PSA in the MK-906 treatment group
suggests that MK-906 exerts a tumor suppressive effect on prostate
cancer cells. While the magnitude of this effect does not appear
similar to medical or surgical castration, it has an excellent
safety profile and potential for preservation of sexual
potency.
The combination a 5.alpha.-reductase inhibitor and antiandrogen,
i.e. of finasteride and flutamide, will exhibit an even greater
effect on suppression of prostate cancer cells/tumors in patients
with stages (A to D) of prostatic adenocarcinoma, in which the
tumors are still androgen-dependent.
The method of preparing the compounds of the present invention,
already described above in general terms, may be further
illustrated by the following examples which should not be construed
as being limitations on the scope or spirit of the instant
invention.
CHAPTER 1
Example 1
Methyl 3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-carboxylate
A suspension of 83.7 g of methyl
3-oxo-4-aza-5.alpha.-androstane-17-carboxylate* and 126.5 g of
benzeneseleninic anhydride in 2.09 l of chlorobenzene was heated at
reflux for 2 hours. The reflux condenser was switched to a
distillation head and the mixture was distilled slowly to remove
water that had formed in the reaction (2 hours). The solution was
evaporated to leave 198 g of wet residue. The residue as a solution
in dichloromethane was washed with saturated aqueous NaHCO.sub.3
solution and saturated NaCl solution, then dried and evaporated to
leave 172.4 g. This material was chromatographed on 2.56 kg of
silica gel eluting first with dichloromethane (5 l) and then with
4:1 dichloromethane acetone. The desired product eluted after 8 l
and amounted to 53.4 g. It was rinsed with diethyl ether and dried
to leave 49.5 g, of the title compound m.p. 278-280.degree. C. In a
similar fashion the following compounds were converted to their
corresponding 1,2-unsaturated derivatives: ##STR63##
Example 2
Methyl
4-methyl-3-oxo-4-aza-5.alpha.-androst-1-ene-17-carboxylate
A suspension of 25 g of the product of Example 1 and 2.25 g of
sodium hydride in 500 ml of dry dimethylformamide was stirred under
nitrogen for 15 minutes. Methyl iodide (15 ml) was added dropwise
and the mixture was stirred for 30 minutes at room temperature.
Additional (5 ml) methyl iodide was added and the mixture was
heated at 50.degree. C. for 2 hours. After cooling the mixture was
diluted with water to a volume of 2 liters. The solid was separated
after cooling and amounted to 25.4 g, m.p. 159-161.degree. C.
In a similar fashion the following compounds were converted to
their corresponding 4-methyl derivatives: ##STR64##
Example 3
S-(2-Pyridyl)
4-methyl-3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-thiocarboxylate
A suspension of 25 g of the product of Example 2 in 125 ml of
methanol was treated with a solution of KOH (*12.5 g) in 12.5 ml of
water. After refluxing for 4 hours, the solution was acidified with
6 NHCl and then was diluted with water. The crude acid (23.32 g)
was separated, dried and had m.p. 300.degree. C.
The crude, dry acid (23 g), triphenylphosphine (36.45 g) and
2,2'-dipyridyldisulfide (30.4 g) were suspended in 138 ml of
toluene with stirring for 3 hours at room temperature. The reaction
mixture was directly chromatographed on a column of 4.5 kg of
silica gel eluting with 9:1 ethyl acetate-acetone to give 20.4 g of
the desired product, m.p. 218-220.degree. C.
Continued elution with acetone gave 5.2 g of the methanol addition
product, S-(2-pyridyl)
1.alpha.-methoxy-4-methyl-3-oxo-4-aza-5.alpha.-androstane-17.beta.-thiocar
boxylate, m.p. 221-223.degree. C. as a by-product.
3A. In a similar fashion the product of Example 1 was converted
into S-(2-pyridyl)
3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-thiocarboxylate, m.p.
230-232.degree. C.
3B. In a similar manner methyl 3-oxo-4-aza-5.alpha.-androstane
17.beta.-carboxylate was converted into S-(2-pyridyl)
3-oxo-4-aza-5.alpha.-androstane-17.beta.-thiocarboxylate, m.p.
232-234.degree. C.
Example 4
N-t-butyl
4-methyl-3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-carboxamide
Anhydrous t-butylamine was added to a suspension of 2.5 g of the
pyridylthioester of Example 3 in 70 ml of tetrahydrofuran. After 60
minutes exposure, the resulting solution was evaporated and the
residue was chromatographed on 125 g of silica gel. Elution with
20:1 ethyl acetate dichloromethane afforded 1.5 g of the product,
m.p. 152-154.degree. C.
When the example is repeated using an appropriate amine and an
appropriate pyridylthioester, the following products were
obtained:
4b: N-t-butyl 3-oxo-4-aza-5.alpha.-androstane-17.beta.-carboxamide,
m.p. 275-276.degree. C.
4c: N-(2,4,4-trimethyl-2-pentyl)
4-methyl-3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-carboxamide,
m.p. 168-170.degree. C.
Example 5
5-Oxo-3,5-secoetian-3,20-dioic acid
To a solution of 200 g of 3-oxo-4-etien-17.beta.-oic acid in 3.5 l
of t-butanol at 80.degree. was added a solution of 198.4 g of
sodium carbonate in 474 ml of water. A warm (65.degree. C.)
solution of 948.5 g of sodium metaperiodate and 6.95 g of
permanganate in 3.5 l of water was added at such a rate that the
reaction mixture was maintained at 80.degree. C. After addition the
mixture was heated at reflux for one hour. The mixture stood at
room temperature overnight. The inorganic salts were removed by
filtration and the cake was washed with 225 ml of water. A solution
of 5% aqueous sodium bisulfite was added to reduce the iodine that
was present. The t-butanol was removed under reduced pressure and
the aqueous residue was acidified with conc. hydrochloric acid. The
separated gum was extracted into dichloromethane and was washed
with 5% aqueous sodium bisulfite, saturated sodium chloride
solution, then dried and concentrated to an off-white residue (214
g). Crystalline material was obtained by suspending the residue in
ether and diluting with hexane to give 152 g, m.p. 189-192.degree.
C.
Example 5B
3-Oxo-4-aza-5-etien-20-oic acid
A suspension of 64.7 g of the dioic acid of Step 5 in 350 ml of
ethylene glycol was treated with 80 ml of liquid ammonia. The
resulting solution was heated at a rate of 3.degree./min. up to
180.degree. C. and was held at that temperature for 15 minutes.
After cooling, 1 liter of water was added and the mixture was
acidified with 10% hydrochloric acid to a pH of 1.5. The product
was removed and washed with water, then air dried to leave 57.5 g
of the product, m.p. 310.degree. C.
Example 5C
3-Oxo-4-aza-5.alpha.-etian-20-oic acid
A solution of 136 g of the 5-acid of Example 5B in 16.32 ml of
acetic acid was hydrogenated at 60.degree. C. in the presence of
platinum catalyst (from 16.32 g of PtO.sub.2) at 40 psig for 3
hours. The catalyst was removed and the solution concentrated to
give 128.2 g of crude product. The material was washed well with 3
l of water then filtered an air dried to leave 125 g of the white
solid, m.p. 310.degree..
This material is also obtained by saponification of methyl
3-oxo-4-aza-5.alpha.-androstane-17.beta.-carboxylate (methyl
3-oxo-4-aza-5.alpha.-etien-17.beta.-oate) in 7% methanolic
potassium hydroxide followed by an acidic work-up.
Example 5D
N-(2,4,4-trimethyl-2-pentyl)3-oxo-4-aza-5.alpha.-androstane-17.beta.-carbox
amide
A solution of 5.0 g of the product of Example 5C, 3.35 g of
dicyclohexylcarbodiimide and 3.18 g of 1-hydroxybenztriazole in 500
ml of dichloromethane was stirred at room temperature overnight.
The solid was separated by filtration and the filtrate was treated
with 2,4,4-trimethyl-2-pentylamine (t-octylamine). This solution
stood at room temperature for 64 hours. A small amount of solid was
removed and the solution was washed successively with 10% aqueous
sodium hydroxide, water, 10% hydrochloric acid and saturated
aqueous sodium chloride. After drying and concentration the crude
product was eluted through 240 g of silica gel with 3:7
acetone-dichloromethane to give 5.5 g of the product, m.p.
250-251.degree. C.
Example 5E
Example 5D is repeated using t-butylamine in place of
2,2,4-trimethyl-2-pentylamine to obtain N-t-butyl
3-oxo-4-aza-5.alpha.-androstane-17.beta.-carboxamide, m.p.
274-276.degree. C.
Example 6
Synthesis of
17.beta.(N-1-adamantyl-carbamoyl)-4-aza-5.alpha.-androst-1-en-3-one
100 mg of the 17-methyl ester (0.305 mmoles) from Example 1 was
suspended in 3.0 ml of THF (dried over molecular sieves 3A), and
then was added 183.0 mg of 1-adamantanamine (1.2 mmoles). The
suspension was cooled to 5-10.degree. C. and then 590 .mu.l of 2.0
M solution, of EtMgBr in THF was added. The resulting mixture was
allowed to stir for 10 minutes, and then refluxed for 1-2 hours
under N.sub.2. The mixture was cooled to 0.degree. C. and then
quenched with saturated solution of NH.sub.4 Cl (about 10 ml.). The
organic layer was separated and the aqueous layer extracted with
three volumes CH.sub.2 Cl.sub.2.
The organic layers were combined, washed 2 times with H.sub.2 O,
twice with saturated sodium chloride, and dried over MgSO.sub.4,
filtered and evaporated to dryness in vacuum. Crystallization from
EtOAc afforded 75.0 mg of product. Recrystallization from MeOH and
drying at 110.degree. C. for 2 hours/0.1 mm gave product, mpt.
305-306.degree. C. Molecular weight (by FAB) showed M.sup.+ =451:
Calculated=451.
Anal. Calcd. for C.sub.29 H.sub.42 N.sub.2 O.sub.2 : C,77.28;
H,9.40; N,6.21. Found: C,76.84; H,9.73; N,5.93.
Example 7
Synthesis of
17.beta.(N-2-adamantyl-carbamoyl)-4-aza-5.alpha.-androst-1-en-3-one
Following the above-described general procedure of Example 6 but
utilizing 2-adamantamine (prepared by aqueous neutralization of the
hydrochloride and EtOAc extraction and isolation) in place of
1-adamantamine, and carrying out the reflux for 7 hours rather than
1-2 hours, the title compound is prepared, mpt. 284-285.degree.
C.
Example 8
Synthesis of
17.beta.(N-1-adamantylcarbamoyl)-4-aza-5.alpha.-androstane-3-one
100.0 mg of the adamantyl derivative produced in Example 6 was
dissolved in 5.0 ml of dry THF. 300 mg of 5% Pd/C was added and the
mixture was hydrogenated for 6.0 hrs. at R.T. at 40 psi. The
mixture was filtered through celite, the cake washed with THF (3
times) and solvent evaporated under vacuum to yield 97.0 mg. of
crude above-titled product. NMR showed absence of olefins. The
crude material was placed on 15.0 g silica gel column, and eluated
with 1:1(CH.sub.2 Cl.sub.2 : acetone).
Collected fractions afforded a single spot material by TLC weighing
77.98 mg. NMR was in excellent agreement with the proposed
structure. Recrystallized from EtOAc to yield 65.59 mg of the
above-titled product, mp. 323-324.degree. C.
Anal. Calcd. for C.sub.29 H.sub.44 O.sub.2 N.sub.2 1/4 H.sub.2 O:
C,76.18; H,9.81; N,6.13. Found: C,75.91; H,9.97; N,6.06.
Example 9
Synthesis of
17.beta.(N-1-adamantylcarbamoyl)-4-methyl-4-aza-5.alpha.-androst-1-en-3-on
e
120 mg of the thiopyridyl ester of Example 3 was suspended in 20 ml
of dry THF, to the suspension was added 175.0 mg of
1-adamantanamine under N.sub.2. The reaction was carried out at
R.T. for 16 hours under N.sub.2. The reaction was monitored by
silica gel TLC, using 1:1 acetone: hexane. The product was
separated on TLC 20 cm.times.20 cm, 1000 .mu.m silica gel plate,
eluted with 1:1 (acetone/hexane). The product was crystallized from
ethyl acetate, to give 50.0 mg of pure material m. pt.
202-205.degree. C. Molecular Weight (FAB) showed 465; Calc: 465.
Recrystallization afforded 19.14 mg of the above-titled product,
m.pt. 202-202.5.degree. C.
Anal. Calcd for C.sub.30 H.sub.44 N.sub.2 O.sub.2.H.sub.2 O:
C,74.64; H,9.60; N,5.80. Found: C,74.32; H,9.47; N,5.89
Example 10
Hydrolysis of
Methyl-3-oxo-4-aza-5.alpha.-androstane-17.beta.-carboxylate
The 17.beta.-androstane carboxylate starting material of Example 1
was hydrolyzed with 7% KOH in isopropanol or aqueous methanol,
followed by an acidic work-up to give the corresponding 17.beta.
carboxylic acid which was utilized in Example 11.
Example 11
N-(1-adamantyl)-3-oxo-4-aza-5.alpha.-androstane-17.beta.-carboxamide
A solution of 5.0 g of the product of Example 10, 3.35 g of
dicyclohexylcarbodiimide and 3.18 g of 1-hydroxybenztriazole in 500
ml of dichloromethane was stirred at room temperature overnight.
The solid was separated by filtration and the filtrate was treated
with 1-adamantamine. This solution stood at room temperature for 64
hours, then filtered, and the solution was washed successively with
10% hydrochloric acid and saturated aqueous sodium chloride. After
drying with MgSO.sub.4, it was filtered and concentrated. The crude
product was eluted through 240 g of silica gel with 3:7
(acetone-dichloromethane) to give 5.5 g of the above-titled
product, m.p. 323-324.degree. C.
Example 12
Synthesis of
Benztriazol-1-yl-3-oxo-4-methyl-4-aza-5.alpha.-androstan-17.beta.-carboxyl
ate
A suspension of 83.7 g of
methyl-3-oxo-4-methyl-4-aza-5.alpha.-androstane-17.beta.-carboxylate.
(See Rasmusson, et al. J. Med. Chem 29, 2298-2315, 1986) was
hydrolyzed with 7% KOH in aqueous methanol, followed by an acidic
work up to give the corresponding 17.beta.-carboxylic acid.
The acid was readily converted into benzotriazyl-1-yl-3-oxo-4
methyl-4-aza-5.alpha.-androstane 17.beta. carboxylate as described
in Example 13. The activated ester (the benzotriazoyl derivative)
was purified on TLC (4 plates, 20 cm.times.20 cm.times.20
cm.times.1000 .mu.m silica gel) eluted with 4:96 (MeOR-CHCl.sub.3).
The isolated product was washed with ether to give the active ester
m.pt. 198-200.degree. C. with decomposition.
Example 13
Synthesis of 17.beta.
(N-1-adamantylcarbamoyl)-4-methyl-4-aza-5.alpha.-androstan-3-one
100.0 mg of the 4-methyl-4-aza-benzotriazole derivative prepared as
described in Example 12, was dissolved in 20.0 ml CH.sub.2
Cl.sub.2. To the clear solution was added 127 mg of 1-adamantamine.
The reaction mixture was stirred overnight at R.T./N.sub.2.
Crystallization from EtOAc after filtering the solution through
Teflon Acrodisc CR afforded 26.32 mg, m.pt. 210-217.degree. C. The
product was further purified on 1.0 g silica gel column (EM silica
gel) with 1:1 (acetone-hexane) as eluant to give after
recrystallization (ethyl acetate) 21.75 mg of white needles of the
above-titled product, m.pt. 203-205.degree. C.
Anal. Calcd. for C.sub.30 H.sub.46 N.sub.2 O.sub.2.1.5 H.sub.2 O:
C,73.58; H,9.68; N,5.62; Found: C,73.15; H,9.30; N,5.67.
Example 14
Diastereomeric Synthesis of
17.beta.(N-exo-2-norbornanylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one)
100.0 mg of the corresponding 4-H thiopyridyl ester of Example 3,
prepared by the procedure of Example 3, but utilizing the 4-H
methyl ester product of Example 1, (See Rasmusson et al. J. Med.
Chem. Vol. 29, pp. 2298-2315 (1986), was dissolved in 3.0 ml of dry
THF under N.sub.2. To the clear solution was added 477 .mu.l of
(.+-.) racemic exo-2-aminonorbornane. Allowed the reaction to
proceed for 16 hours at R.T./N.sub.2. The reaction mixture was
evaporated to dryness in vacuum. The residue was dissolved in
chloroform. The organic layer was washed with 2.5 N HCl acid (3
times); 3 times with water; 3 times with saturated NaCl solution,
dried over MgSO.sub.4, filtered and evaporated to dryness in vacuum
to afford 56.3 mg of a racemic diastereomeric mixture.
The crude product was chromatographed on TLC (2 plates, 20
cm.times.20 cm.times.500 .mu.m silica gel) eluted with 70:30
(CHCl.sub.3 :acetone) to yield 43.4 mg of the above-titled product.
Recrystallization from EtOAc yielded 30 mg product, m.pt
245-245.9.degree. C.
NMR (CDCl.sub.3) confirmed the above structure. FAB mass spectrum
calcd. for C.sub.26 H.sub.38 O.sub.2 N.sub.2 : m/e 411; Found: 411.
Anal. Calcd. for C.sub.26 H.sub.38 O.sub.2 N.sub.2.H.sub.2 O:
C,72.82; H,9.40; N,6.58. Found: C,73.21; H,9.20; N,6.25.
Example 15
Synthesis of
17.beta.(N-1-adamantylmethylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one
200.0 mg of the 4-H thiopyridyl aza steroid, used in Example 14,
was suspended in 2.0 ml of dry THF.
To the suspension was added 400 .mu.l of 1-aminomethylene
adamantane via syringe at R.T./N.sub.2. After several minutes, a
yellow clear solution resulted and after 1/2 hr., precipitation
occurred. The reaction was allowed to proceed overnight/N.sub.2.
Diluted with CH.sub.2 Cl.sub.2, washed with 10% NaOH, two times,
then with H.sub.2 O two times, followed by 10% HCl (two times),
H.sub.2 O (two times), and finally two times with satd. NaCl
solution.
The organic layer was dried over MgSO.sub.4, filtered, concentrated
in vacuo to obtain the product, as shown by NMR, recrystallized
from EtOAc, to yield 149.0 mg product, m.pt 255-257.degree. C. with
decomposition.
FAB Mass Spectrum, Calcd: m/e 464+1=465: Found 465.
Example 16
Synthesis of
17.beta.(N-2-adamantylcarbamoyl)-4-aza-5.alpha.-androstan-3-one
A mixture of 1.09 grams
17.beta.-(N-2-adamantylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one
(See Example 10 for preparation), 150 ml of ethanol, and 1.0 g. of
30% Pd/C was hydrogenated overnight with shaking under 45 psig.
hydrogen pressure. The suspension was filtered to remove catalyst,
and evaporated to dryness to yield a grey residue. This was
chromatographed by elution on a 200 ml silica gel column with 40:60
acetone/methylene chloride eluant to yield 1.0 g of solid, mp.
294-296.degree. C.
Anal. Calcd. for C.sub.29 H.sub.44 N.sub.2 O.sub.2.0.2H.sub.2 O;
Calcd. C, 76.33; H, 9.80; N, 6.14; Found C, 76.23; H, 9.86; N,
5.92; Mass Spec. Analysis by electron impact showed MW of 452.
Example 17
Synthesis of
17.beta.-(N-2-adamantylcarbamoyl)-4-aza-4-methyl-5.alpha.-androst-1-en-3-o
ne
A suspension of 500 mg of
17.beta.-(N-2-adamantylcarbamoyl)-4-aza-5.alpha.-androst-1-en-3-one,
as prepared in Example 16, 10 ml sieve-dried DMF, 140 mg NaH, were
heated and stirred at 70.degree. C. under a nitrogen atmosphere for
18 hours. Cooled to room temperature and then added 0.4 ml methyl
iodide dropwise with stirring which was continued at 50.degree. C.
for 3 hours. The reaction mixture was then treated by cooling to
room temperature, followed by the addition of 15 ml water. The
mixture was extracted with 3.times.20 ml of CH.sub.2 Cl.sub.2. The
organic layers were combined, washed with brine, dried and
evaporated to yield a white crystalline residue. Recrystallization
from ethyl acetate/CH.sub.2 Cl.sub.2 yielded a pure white solid, mp
246-248.degree. C.
Analysis calculated for C.sub.30 H.sub.44 N.sub.2
O.sub.2.0.3H.sub.2 O; Calcd. C, 76.65; H, 9.56; N, 5.95; Found C,
76.50; H, 9.75; N. 5.84 ; Mass spectroscopy showed a molecular
weight of 464.
Example 18
Synthesis of
17.beta.-(N-2-adamantylcarbamoyl)-3-oxo-4-methyl-4-aza-5.alpha.-androstane
17.beta.-(N-2-adamantylcarbamoyl)-4-methyl-4-aza-androsten-1-en-3-one,
(200 mg) as prepared in Example 17, were placed into 25 ml absolute
ethanol with 200 mg 30% Pd/C hydrogenation catalyst. The suspension
was rocked overnight under 40 psig hydrogen pressure.
The suspension was filtered, and the filtrate evaporated to
dryness. The residue was recrystallized from hot ethyl acetate to
give a white crystalline solid, mp. 113-115.degree. C. Calcd. for
C.sub.32 H.sub.5 ON.sub.2 O.sub.3.0.5 EtOAc
Calcd: C, 75.25, H, 9.86, N, 5.48; Found C, 75.07; H, 9.52; N,
5.28; Mass spectroscopy depicted a molecular weight of 466 for the
non-solvated molecule.
Example 19
Synthesis of 17.beta.-(N-methyl-N-2-adamantyl)
carbamoyl-4-methyl-4-aza-androst-1-en-3-one
17.beta.-(N-2-adamantyl)carbamoyl-4-aza-androst-1-en-3-one (5.0 g)
and 1.5 g sodium hydride in 100 ml dry DMF were stirred under dry
nitrogen for 3 hours at 40.degree. C. The reaction was cooled to
room temperature and about 4 ml of methyl iodide was added dropwise
and allowed to stir at room temperature for one hour. The reaction
was cooled in an ice bath and a large excess of about 250 ml, water
was added. The aqueous mixture was extracted with CH.sub.2 Cl.sub.2
(3.times.100 ml), the organic extracts combined, washed with
H.sub.2 O, brine, and then evaporated to dryness to yield crude
product. The crude product was eluted on an HPLC column (Si gel)
with 10/1 acetone/CH.sub.2 Cl.sub.2 to yield 2 peaks having
retention times of 3 CV(B) and 3.8 CV(A). Peak (A) was analyzed as
per the 4-methylaza titled product of Example 15. The second
product (B) was analyzed as the
4-methylaza-17.beta.-(N-methyl-N-2-adamantyl/carbamoyl analog, i.e.
the titled compound, mp. 163-165.
Calcd. for C.sub.31 H.sub.46 N.sub.2 O.sub.2 ; Calcd. C, 77.77; H,
9.68; N, 5.85; Found C, 77.29; H, 9.79; N, 5.77; Mass spectrometry
showed a molecular weight of 478.
Example 20
Synthesis of 17.beta.-(N-methyl-N-2-adamantylcarbamoyl)
4-aza-4-methyl-androstan-3-one
The crude reaction mixture from Example 19 (4.6 g) was dissolved in
200 ml ethanol and together with 1.0 g 30% Pd/C was hydrogenated
under 40-45 Psig a hydrogen atmosphere at room temperature
overnight. The mixture was filtered, residue washed with ethanol.
The ethanol solution was evaporated to dryness to yield a crude
mixture. Recrystallized from CH.sub.2 Cl.sub.2 /diethyl
ether/hexane to yield 800 mg of the pure monomethyl androstane
compound of Example 16, mp 113-115.degree. C. Second and third
crops were combined with mother liquor and treated by HPLC as in
Example 17 to yield the dimethylated title compound, mp
180-182.degree. C.
Anal. Calcd. for C.sub.31 H.sub.48 N.sub.2 O.sub.2 ; Calcd. C,
77.45; H, 10.06; N, 5.83; Found C, 77.26; H, 9.87; N, 5.82; Mass
spectrometry showed a molecular weight of 480.
Example 21
N-t-Butyl Androst-3,5-diene-17.beta.-carboxamide-3-Carboxylic
Acid
(a) N-t-butyl androst-3,5-diene-3-bromo-17.beta.-carboxamide
To a solution of oxalic acid (0.0011 mol, 0.1 g) and oxalyl bromide
(0.0211 mol, 3 ml) in 15 ml of sieve dried toluene was added over a
one hour period 1 g (0.003 mol) of androst-4-ene-3-one
17.beta.-carboxylic acid. The reaction was stirred at room
temperature for 2 hours and then it was concentrated in vacuo. The
excess oxalyl bromide was removed by azetoroping with toluene. The
resulting brown oil was redissolved in toluene, cooled to 0.degree.
C. and then 10 ml t-butylamine (7.0 g) in 30 ml of toluene was
added dropwise over 15 minutes. Once the addition was complete, the
reaction was stirred at 0.degree. C. for 15 minutes and then it was
kept at -20.degree. C. for 19 hours. The reacton mixture was
allowed to warm to room temperature and then stirred at 25.degree.
C. for one hour. The volatiles were removed in vacuo. The residue
was partitioned between chloroform/water, the layers were shaken
together and separated and then the aqueous phase was
back-extracted twice with chloroform. The combined organic extracts
were washed with water (2.times.) and then dried with anhydrous
magnesium sulfate. The crude product was purified by flash
chromatography on silica, eluting with 20% ethyl acetate in hexane,
to give 1.06 g of the title compound, a white solid.
(b) N-t-Butyl Androst-3,5-diene-17.beta.-carboxamide-3-carboxylic
acid
To a solution of N-t-Butyl
Androst-3,5-diene-3-bromo-17.beta.-carboxamide (0.5 g, 0.00115 mol)
in 5 ml of tetrahydrofuran, cooled to -78.degree. C. (dry
ice/acetone bath) under argon, was added dropwise 1.5 ml (0.00375
mol) of a 2.5 M solution of n-butyl lithium in hexane. The reaction
mixture was stirred at this temperature for one hour and then
carbon dioxide was bubbled into the reaction for 45 minutes, via a
concentrated sulfuric acid tower. The reaction mixture was allowed
to warm to room temperature and then it was diluted with water,
aqueous HCl solution and chloroform. The layers were shaken
together and separated, with the aqueous phase being back-extracted
with chloroform (2.times.). The combined organic extracts were
washed with water (2.times.), and brine (1.times.) and then dried
with anhydrous magnesium sulfate. The solvents were removed under
reduced pressure give 0.6 g of a crude solid. This material was
slurried with hexane and a white solid was isolated (0.43 g). The
title compound was recrystallized from acetonitrile, m.p.
247-250.degree..
CHAPTER 2
Example 1
Methyl 3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-carboxylate
A suspension of 83.7 g of methyl
3-oxo-aza-5.alpha.-androstane-17.beta.-carboxylate* and 126.5 g of
benzeneseleninic anhydride in 2.09 l of chlorobenzene was heated at
reflux for 2 hours. The reflux condenser was switched to a
distillation head and the mixture was distilled slowly to remove
water that had formed in the reaction (2 hours). The solution was
evaporated to leave 198 g of wet residue. The residue as a solution
in dichloromethane was washed with saturated aqueous NaHCO.sub.3
solution and saturated NaCl solution, then dried and evaporated to
leave 172.4 g. This material was chromatographed on 2.56 kg of
silica gel eluting first with dichloromethane (5 liters) and then
with 4:1 dichloromethane-acetone. The desired product was eluted
with 8 liters of the above-mixed solvent and evaporated to dryness
in vacuo to yield 53.4 g solid. It was washed with diethyl ether
and dried to leave 49.5 g of the above-titled product, m.p.
278-280.degree. C.
Example 2
S-(2-Pyridyl)-3-oxo-4-aza-5.alpha.-androst-1-ene-17.beta.-thiocarboxylate
A suspension of 25.0 g of the above product from Example 1 was
saponified with 12.5 g of KOH in 150.0 ml of 5:1 CH.sub.3
OH--H.sub.2 O under reflux conditions for 4 hours/N.sub.2. The
mixture was cooled to 25.degree. C. and acidified to pH<2. Water
(175 ml) was added gradually with stirring to leave a crystalline
precipitate which was collected and washed with water.
After drying, the product amounted to 25 g., m.pt 313-315.degree.
C. with decomposition.
The crude dry acid (23.0 g) was suspended in 210 ml of toluene, and
to the suspension was added triphenylphosphine (56.0 g) and
2,2'-dipyridyl disulfide (48.3 g), and the mixture was stirred at
24.degree. C. overnight/N.sub.2. The reaction mixture was placed on
a column of silica gel (1.3 kg) and was eluted with 1:1
(acetone/CH.sub.2 Cl.sub.2). The desired thioester eluted slowly,
and after rinsing with ether, yielded 36.8 g of the above-titled
product, m.p. 232-235.degree. C.
Example 3
22-Methyl-4-aza-21-nor-5.alpha.-chol-1-ene-3,20-dione ##STR65##
To a solution of 7.2 g of
S-(2-pyridyl)-3-oxo-4-aza-5.alpha.-androst-1-ene-17.alpha.-thiocarboxylate
in 288 ml of tetrahydrofuran was-added at -78.degree. C. 33.6 ml of
1.3M S-butylmagnesium chloride. After 30 minutes at -78.degree. C.
the solution came to room temperature and was treated with
saturated aqueous NaCl solution. The product was extracted into
dichloromethane and was washed with saturated aqueous NaCl solution
and 10% aqueous NaOH solution, then dried and concentrated. The
residue was eluted through 430 g of silica gel with 9:1
dichloromethane-acetone to give 4.5 g of the product, m.p.
246-249.degree. C.
When the procedure is repeated using the following reagents, the
indicated product is obtained.
______________________________________ Starting Material Reagent
Product ______________________________________ S-(2-pyridyl)3-
2-pyrrolyl mag- 17.beta.-(2-pyrrolyl- oxo-4-aza-5.alpha.- nesium
chloride carbonyl)-4-aza- androst-l-ene- 5.alpha.,-androst-1-ene-
17.beta.-thiocarboxylate 3-one m.p. 294-296.degree. C.
S-(2-pyridyl)3- sec-butyl mag- 4,22-dimethyl-4-
oxo-4-methyl-5.alpha.- nesium chloride aza-21-nor-5.alpha.-
androst-1-ene-17.beta.- chol-1-ene-3,20-dione thiocarboxylate m.p.
134-136.degree. C. S-(2-pyridyl)3- 2-pyrrolyl mag-
4-methyl-17.beta.-(2- oxo-4-methyl-4- nesium chloride
pyrrolylcarbonyl)- aza-5.alpha.-androst- 4-aza-5.alpha.-androst-
1-ene-17.beta.-thio- 1-ene-3-one carboxylate m.p. 234-238.degree.
C. S-(2-pyridyl)3- isobutyl mag- 23-methyl-4-aza-
oxo-4-aza-5.alpha.- nesium chloride 21-nor-5.alpha.-
androst-ene-17.beta.- cholane-3,20- thiocarboxylate dione m.p.
220-222.degree. C. ______________________________________
Example 4
22-Methyl-4-aza-21-nor-5.alpha.-chol-1-ene-3,20-dione ##STR66##
A solution of 21 g of
22-methyl-4-aza-21-nor-5.alpha.-cholane-3,20-dione and 29.49 g of
benzeneseleninic anhydride in 552 ml of chlorobenzene was refluxed
with water separation for 4 hours. The mixture was concentrated and
the residue was redissolved in dichloromethane. After washing with
10% aqueous sodium hydroxide, then 10% hydrochloric acid and
saturated aqueous sodium chloride the solution was dried and
concentrated to 45 g of yellow residue. This was chromatographed on
1.5 kg of silica gel packed in dichloromethane and eluted with
ethyl acetate to give 10.6 g of the product, m.p. 248-251.degree.
C.
When the procedure is repeated using
23-methyl-4-aza-21-nor-5.alpha.-cholane-3,20-dione as starting
material the product obtained is
23-methyl-4-aza-21-nor-5.alpha.-chol-1-ene-3,20-dione, m.p.
283-286.degree. C.
Example 5
17.beta.-(phenylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one
To a stirred suspension of 43 g of
S-(2-pyridyl)-3-oxo-4-aza-5-alpha-androst-1-ene-17-beta-thiocarboxylate
in 500 ml of anhydrous tetrahydrofuran (THF) was added at
-78.degree. C. a THF solution of 157 ml of 2N phenylmagnesium
chloride over 60 minutes. After stirring at -78.degree. C. for 60
minutes, the mixture was brought to -30.degree. C. and was quenched
by addition of 10% HCl while maintaining the temperature below
-20.degree. C. After warming to 0.degree. C., the mixture was
diluted with 2000 ml of water and extracted with 4000 ml of
dichloromethane in portions. The organic layer was washed
sequentially with water, 1N sodium hydroxide, water and saturated
sodium chloride solution. Drying with MgSO4 and concentration
afforded 37.5 g of crude product. Recrystallization from
dichloromethane/ethyl acetate gave the title phenyl ketone (30.4 g,
77% yield). m.p. 290-291.degree. C.
______________________________________ Calc Found
______________________________________ N 3.61 3.56 C 77.48 77.16 H
8.26 8.19 ______________________________________
Example 6
17-beta-4-fluorophenycarbonyl-4-aza-5-alpha-androst-1-ene-3-one
The procedure of Example 5 was repeated except using
p-fluorophenylmagnesium bromide as the Grignard reagent and the
title compound was obtained. m.p. 315-315.5.degree. C.
Example 7
17.beta.-(cyclohexylcarbonyl)-4-aza-5.alpha.-androst-1-ene-3-one
To a suspension of 34.8 g of the thiopyridyl ester of Example 2 in
700 ml of anhydrous THF was added at -65 degrees C. 130 ml of a 2 M
ether solution of cyclohexyl magnesium chloride over a period of 20
minutes. After stirring at -70 degrees C. for 60 minutes the
solution was warmed and stirred at -10 degrees C. for 60 minutes.
The mixture was diluted with 500 ml of dichloromethane and then
dropwise with dichloromethane, the phases were separated and the
organic layer was treated sequentially with water, 1 N sodium
hydroxide, water and saturated sodium chloride solution. The
organic solution was decolorized with charcoal, filtered and
concentrated to a residue which was crystallized from ethyl acetate
to give 28.2 of the title compound, m.p. 271.5-277 degrees C.
Example 8
The title compound of Example 7 was also prepared by the following
procedure.
To a mixture of 150 g of methyl
3-oxo-4-aza-5-alpha-androst-1-ene-17-beta-carboxylate in 2800 ml of
anhydrous THF was added with stirring at less than 0 degrees C.
internal temperature 678 ml of a 2 N ether solution of cyclohexyl
magnesium chloride. The solution was then refluxed for 6 hours. The
cooled (less than 10 degrees C.) reaction mixture was acidified
with 10% HCl solution and was extracted with dichloromethane. The
organic layer was washed sequentially with water, saturated NaHCO3
solution and saturated NaCl solution. Drying (MgSO4) and
evaporation left 163 g of crude cyclohexyl ketone.
Recrystallization from dichloromethane/ethylacetate gave 131 g of
the pure material.
m.p. 269-270 degrees C.
______________________________________ % Calc. Found
______________________________________ N 3.61 3.61 C 77.37 77.37 H
9.74 10.13 ______________________________________
Example 9
17-beta-(cyclopentylcarbonyl)-4-aza-5-alpha-androst-1-ene-3-one
When the procedure of Example 7 or 8 was repeated using
cyclopentylmagnesium chloride, the title compound was obtained:
m.p. 272-273 degrees C.
______________________________________ Calc. Found
______________________________________ N 3.66 3.78 C 75.25 74.89 H
9.60 9.54 ______________________________________
Example 10
17-beta-(cyclobutylcarbonyl)-4-aza-5-alpha-androst-1-ene-3-one
When the procedure of Example 7 or 8 was repeated using
cyclobutylmagnesium chloride, the title compound was obtained:
m.p. 288-289 degrees C.
______________________________________ % Calc Found
______________________________________ N 3.94 3.87 C 77.71 78.06 H
9.36 9.61 ______________________________________
Example 11
Synthesis of
17-.beta.-(4-Phenylbenzoyl)-4-aza-5.alpha.-androst-1-en-3-one
To a suspension of 258.0 mg of dry activated magnesium chips in 5.0
ml of dry THF was added 932.0 mg of 4-bromobiphenyl in 5.0 ml of
dry THF under N.sub.2. The reaction was run in an ultrasonic bath
at a temperature range of 24-30.degree. C. To the well-agitated
mixture was added dropwise 30 .mu.l of 1,2-dibromoethane/N.sub.2.
The reaction was allowed to proceed for 1-11/2 hours at 28.degree.
C./N.sub.2. The concentration of the Grignard reagent was 4.0
mmoles in 10.0 ml of dry THF.
The steroid from Example 2 (205.0 mg, 0.5 mmol of thiopyridyl
ester) was suspended in 2.0 ml of dry THF, cooled to -80.degree. C.
and the above Grignard 3.80 ml was added via syringe to the
steroidal suspension over 5-10 minutes/N.sub.2. The reaction was
allowed to proceed for 1 hour at -80.degree. C./N.sub.2 and then at
-10.degree. C. for an additional hour/N.sub.2. The solution was
diluted with 10.0 ml of methylene chloride and quenched with
saturated aqueous solution of NH.sub.4 Cl to pH=4. The organic
layers were separated, washed 3 times with water, 3 times with
saturated sodium chloride, dried over MgSO.sub.4, filtered, and
evaporated under vacuum to afford 156.2 mg of crude product.
Crystallization from EtOAc gave the above-titled product in 98.58
mg, m.pt. 290.degree. C.-290.5.degree. C.
Anald. Calcd. for C.sub.31 H.sub.35 NO.sub.2 : C,82.08; H,7.78;
N,3.09; Found: C,81.84; H,8.01; N,3.06. FAB: Calc. for C.sub.31
H.sub.35 NO.sub.2 : 453; Found: 453.
Example 12
17-.beta.-(3-Phenylbenzoyl)-4-aza-5.alpha.-androst-1-en-3-one
To a suspension of 258.0 mg of dry activated magnesium chips in 8.0
ml of dry THF was added 932.0 mg of 3-bromobiphenyl in 2.0 ml of
dry THF under N.sub.2. The reaction was run in an ultrasonic bath
at a temperature range of 24-30.degree. C. To the well-agitated
mixture was added dropwise 30 microliters of
1,2-dibromoethane/N.sub.2. The concentration of the Grignard
reagent was 4 mmoles in 10.0 ml of dry THF.
The steroid from Example 2, 205.0 mg (0.5 mmoles) was suspended in
2.0 ml of dry THF, cooled to -80.degree. C. and the above prepared
Grignard, 3.80 ml, was added via syringe to the steroidal
suspension over 5-10 minutes/N.sub.2. The reaction was allowed to
proceed for 1 hour at -80.degree. C./N.sub.2 and then at
-10.degree. C. for an additional hour/N.sub.2. The solution was
diluted with 10.0 ml of methylene chloride and quenched with a
saturated aqueous solution of NH.sub.4 Cl to pH=4. The organic
layers were separated, washed 3 times with water, 3 times with
saturated sodium chloride, dried over MgSO.sub.4, filtered, and
evaporated under vacuum. Crystallization from ethyl acetate
afforded 122.84 mg of product. The material was purified on 20.0 g
of silica gel column using 70:30 (CHCl.sub.3 -acetone) as eluant,
to give a single spot material 117.0 mg of the above-titled
compound, m.pt. 184-185.degree. C.
Anald. Calcd. for C.sub.31 H.sub.35 NO.sub.2 : C,82,08; H,7.78;
N,3.09; Found: C,82.28; H,8.04; N,2.98. FAB: Calcd. for C.sub.31
H.sub.35 NO.sub.2 : 453; Found: 453.
Example 13
Synthesis of
17-.beta.-(4-Methylthiobenzoyl)-4-aza-5-.alpha.-androst-1-en-3-one
To a suspension of 250.0 mg of dry activated magnesium chips in 8.0
ml of dry THF was added 812.0 mg of p-bromophenyl methyl sulfide in
3.0 ml of dry THF under N.sub.2. The reaction was run in an
ultrasonic bath at a temperature range of 24-30.degree. C. To the
well-agitated mixture was added dropwise 40 .mu.l of
1,2-dibromoethane/N.sub.2. The reaction was allowed to proceed for
1 to 11/2 hours at 28.degree. C./N.sub.2. The concentration of the
Grignard reagent was 4.0 mmoles in 10 ml of dry THF.
The steroid from Example 2, i.e. the pyridylthio ester, 205 mg, was
suspended in 2.0 ml of dry THF, cooled to -80.degree. C. and the
above prepared Grignard was added via syringe to the steroidal
suspension in 5-10 minutes/N.sub.2. The reaction was allowed to
proceed for 1 hour at -80.degree. C./N.sub.2 and then at
-10.degree. C. for an additional hour/N.sub.2. The solution was
diluted with 10.0 ml of methylene chloride, and quenched with
saturated aqueous solution of NH.sub.4 Cl to pH=4. The organic
layers were separated, washed 3 times with water; 3 times with
saturated sodium chloride, dried over MgSO.sub.4, filtered, and
evaporated under vacuum to afford 105.0 mg of crude product.
The crude product was chromatographed on TLC (one plate, 20
cm.times.20 cm.times.20 cm.times.1000 .mu.m silica gel) eluted with
80:20 (CH.sub.2 Cl.sub.2 -acetone) to afford 66.0 mg of single spot
material. Crystallization from EtOAc afforded 45.0 mg of the
above-titled compound, m.pt. 286-287.degree. C.
FAB for C.sub.26 H.sub.33 NO.sub.2 S (Calcd.) 424; Found 424.
Example 14
Synthesis of 17-.beta.-(4-methylsulfinylbenzoyl) and
-(4-methylsulfonylbenzoyl)-4-aza-5.alpha.-androst-1-en-3-one
A. Oxidation
19.91 mg of the methylthio product from Example 13 was dissolved in
2.5 ml of CH.sub.2 Cl.sub.2, cooled to 0-(-2).degree. C. and was
treated with a solution 9.6 mg of m-chloroperbenzoic acid in 1.0 ml
of CH.sub.2 Cl.sub.2 over a period of 4 minutes. After stirring for
1 hour at 0-(-2).degree. C., the reaction was diluted with 10 ml.
CH.sub.2 Cl.sub.2. The layers were washed subsequently with 2.5%
NaHCO.sub.3, H.sub.2 O and saturated NaCl solutions. The organic
layer was dried over MgSO.sub.4 overnight, filtered and evaporated
in vacuo to yield 17 mg product. Crystallization from EtOAc gave
11.8 mg of the above-titled compound, a solid, mp.
313-313.5.degree. C. (with dec.).
Anal. Calcd. for C.sub.26 H.sub.33 NO.sub.3 S.1/4H.sub.2 O:
C,70.31; H,7.60; N,3.15; Found: C,70.47; H,7.70; N,3.00. FAB for
C.sub.26 H.sub.33 NO.sub.3 S (Calcd. 440); Found 440.
Sulfone
Fifteen percent (15%) of the corresponding sulfone,
17.beta.-(4-methylsulfonyl benzoyl) derivative, was isolated by
chromatography from the reaction as a byproduct. Recrystallized
from EtOAc to yield a solid, mp. 279-279.5.degree. C. Molecular
weight by FAB showed 456; calculated 456.
Anal. for C.sub.26 H.sub.33 NO.sub.4 S.0.25 H.sub.2 O Calc:
C,67.87; H,7.28; N,3.04. Found: C,67.96; H,6.72; N,2.95.
Example 15
Synthesis of
17-.beta.-(4-acetoxymethylthiobenzoyl)-4-aza-5.alpha.-androst-1-en-3-one
Trifluoroacetic anhydride (165 .mu.l) was dissolved in 780 .mu.l of
acetic anhydride and kept for 5 hours at room temperature (RT).
To 300 .mu.l of the above solution of mixed anhydrides was added
34.15 mg pure sulfoxide from Example 14 with stirring. A few
minutes later 54.0 .mu.l of 2,6-lutidine was added and the reaction
was allowed to stir at RT/N.sub.2 for 17 hours.
The liquid anhydrides were removed under reduced pressure and the
remaining residue extracted (4 times with CHCl.sub.3). The
CHCl.sub.3 extracts were washed subsequently with dilute HCl; 5%
NaHCO.sub.3 solution, 3 times; 3 times with H.sub.2 O; and finally
with saturated NaCl solution, and then dried over MgSO.sub.4
filtered and evaporated the solution to dryness in vacuo to yield
42.1 mg of crude product.
The crude product from Step A was purified by chromatography on
silica gel using 95:5 (CHCl.sub.3 -acetone) as eluant and then
crystallizing the obtained solid from EtOAc to yield 17.8 mg of the
above-titled compound as crystals, m.pt. 235-236.degree. C.
(dec.).
Anal. Calcd. for C.sub.28 H.sub.35 O.sub.4 NS.1/4 H.sub.2 O:
C,68.57; H,7.40; N,2.86; Found: C,69.02; H,7.39; N,2.73. FAB for
C.sub.28 H.sub.28 O.sub.4 NS calcd.: 482; Found 482. The NMR
(proton) was in agreement with the assigned product structure.
Example 16
Synthesis of
17.beta.(4-mercaptobenzoyl)-4-aza-5.alpha.-androst-1-en-3 one
40.0 mg of the acetoxy-methyl-thio derivative from Example 15 was
suspended in 3.0 ml of isopropanol. The reaction mixture was
flushed several times with N.sub.2, and with vacuum, and the system
kept under nitrogen atmosphere. To the above mixture was added 40.0
mg of K.sub.2 CO.sub.3 in 2.00 ml of water (free of oxygen) via
syringe, and the temperature of the reaction mixture was allowed to
rise to 80.degree. C. under gentle reflux under slight vacuum for
10 minutes, and then under N.sub.2 for 1 hour. After 1 hour, the
reaction mixture was a clear yellow solution. It was brought to
R.T., cooled to 0-5.degree. C. and quenched with 2.5 N HCl
acid/N.sub.2. The reaction mixture was extracted 4 times with
CH.sub.2 Cl.sub.2. The organic layer was washed with H.sub.2 O 4
times; 3 times with saturated salt solution, and finally dried over
MgSO.sub.4. Filtered and evaporated to dryness in vacuo to yield
36.9 mg of crude product. The crude product was dissolved in 2.0 ml
of CHCl.sub.3, filtered through Teflon (Acrodisc CR) and purified
by preparative HPLC on silica gel and eluted with 60:40 (CH.sub.2
Cl.sub.2 -acetone). Crystallization, from EtOAc afforded a single
spot material, 20.7 mg of the above-titled compound, m.pt.
285-286.degree. C.
Anal. Calcd. for C.sub.25 H.sub.31 O.sub.2 NS.1/2 H.sub.2 O:
C,72.19; H,7.69; N,3.24; Found: C,71.82; H,7.43; N,3.26. FAB:
Calcd. for C.sub.25 H.sub.31 O.sub.2 NS: 410; Found: 410.
Example 17
Synthesis of
17-.beta.-(4-Dimethylaminobenzoyl)-4-aza-5-.alpha.-androst-1-en-3-one
To a suspension of 291.0 mg of dry activated magnesium chips in 8.0
ml of dry THF was added 800.0 mg of 4-bromo-N,N-dimethylaniline in
2.0 ml of dry THF under N.sub.2. The reaction was run in an
ultrasonic bath at a temperature range of 24-30.degree. C. To the
well-agitated mixture was added dropwise 30 .mu.l of
1,2-dibromoethane/N.sub.2. The reaction was allowed to proceed for
1 to 11/2 hours at 28.degree. C./N.sub.2. The concentration of the
Grignard reagent was 4.0 mmoles in 10.0 ml of dry THF.
The steroid from Example 2 (205 mg of pyridyl thioester) was
suspended in 2.0 ml of dry THF, cooled to -80.degree. C. and the
above Grignard 3.8 ml (3 equivalents) was added via syringe to the
steroidal suspension over 5-10 minutes/N.sub.2. The reaction was
allowed to proceed for 1 hour at -80.degree. C./N.sub.2 and then at
-10.degree. C. for an additional hour/N.sub.2. The solution was
diluted with 10.0 ml of methylene chloride and quenched with a
saturated aqueous solution of NH.sub.4 Cl to pH=4. The organic
layers were separated, washed 3 times with water 3 times with
saturated sodium chloride, dried over MgSO.sub.4, filtered, and
evaporated under vacuum to afford 151.3 mg of crude product.
Crystallization from ethyl acetate gave 124.5 mg of the
above-titled compound, m.pt. 268.5-269.degree. C.
FAB: Calcd. C.sub.27 H.sub.36 N.sub.2 O.sub.2 : 421; Found: 421.
The NMR (proton in CDCl.sub.3) confirmed the assigned
structure.
Example 18
General Procedure for Preparing Protected Silyl Derivatives
1.0 mole of phenol or its derivatives, or 1 mole of alcohol is
treated with 1.5 liters of dry methylene chloride. To the clear
solution is added dry 3.0 moles of imidazole/N.sub.2. The clear
solution is cooled to 0.degree. C./N.sub.2, and 2.0 moles of
t-butyl dimethyl chlorosilane in 300.0 ml of dry methylene chloride
is added dropwise at 0.degree. C./N.sub.2. Towards the end of the
addition, precipitation occurs. The ice bath is removed, and the
reaction is allowed to proceed overnight at R.T./N.sub.2. Filter,
wash the cake with cold CH.sub.2 Cl.sub.2 solution, and the solvent
is evaporated in vacuo to afford crude product. The crude product
was readily purified by filtering through a silica gel column. (1
gr. of crude product per 100 g of silica gel, using CH.sub.2
Cl.sub.2 as eluant) This method gives about 99% of pure silyl
derivatives of phenols and alcohols.
Example 19
Synthesis of
17-.beta.-(4-Hydroxybenzoyl)-4-aza-5-.alpha.-androst-1-ene-3-one
A. Grignard Reaction
To a suspension of 1.22 g of dry activated magnesium chips in 20.0
ml of dry THF was added 5.6 g of 1-bromo-4-(tertiary-butyl dimethyl
silyloxy)benzene (prepared from p-bromophenol by the General
Procedure detailed above) in 10.0 ml of THF under N.sub.2. The
reaction was run in an ultrasonic bath at a temperature range of
24-30.degree. C. To the well-agitated mixture was added dropwise
150 .mu.l-200 .mu.l of 1,2-dibromoethane/N.sub.2. The reaction was
allowed to proceed for 1-11/2 hours at 28.degree. C./N.sub.2. The
concentration of the Grignard reagent formed was 19.5 mmoles in
30.0 ml of dry THF.
The steroid from Example 2 (1.02 g, 2.49 mmoles) was suspended in
20.0 ml of dry THF, cooled to -80.degree. C. and the above-prepared
Grignard (11.5 ml) was added via syringe to the steroidal
suspension in 5-10 minutes/N.sub.2. The reaction was allowed to
proceed for 1 hour at -80.degree. C./N.sub.2, and then at
-10.degree. C. for an additional hour/N.sub.2. The reaction
solution was diluted with 10.0 ml of methylene chloride and
quenched with a saturated aqueous solution of NH.sub.4 Cl to pH=4.
Organic layers were separated, washed 3 times with H.sub.2 O, 3
times with saturated sodium chloride, dried over MgSO.sub.4,
filtered, and evaporated under a vacuum to a yellow color solid.
Crystallization from ethyl acetate afforded 607 mg of product m.p.
248-249.degree. C.
Anal. Calcd. for C.sub.31 H.sub.45 O.sub.3 NSi: C,73.32; H,8.93;
N,2.75 Found: C,73.27; H,8.99; N,2.75. FAB: Found 508; Calc.
508.
B. Desilylation
Dissolved 1.3 g of product from above step A in 20.0 ml of dry THF.
Cooled to -5.degree. C. and added 437 .mu.l of glacial acetic
acid/N.sub.2. To the cold solution at -5.degree. C. was added via
syringe 3.0 ml tetra-n-butylammonium fluoride dropwise under
N.sub.2 atmosphere. Allowed the reaction to proceed under stirring
for 11/2-2 hours at 0.degree. to -5.degree. C./N.sub.2. The
reaction mixture was poured into a 2-layer mixture of ethyl
acetate/sodium bicarbonate saturated solution at 0.degree. C. The
water layer was separated and further extracted with EtOAc 3 times
and with CH.sub.2 Cl.sub.2 (3 times).
The organic layers were combined, washed 3 times with H.sub.2 O, 1
time with saturated sodium chloride solution, and dried over
MgSO.sub.4, filtered and evaporated to dryness under vacuum. The
crude product was crystallized from ethyl acetate to afford 977.9
mg, and further recrystallized from methanol to afford 842.3 mg of
the above-titled product, m.pt. 296-297.degree. C.
Anal. Calcd. for C.sub.25 H.sub.31 NO.sub.3.1/3 H.sub.2 O: C,75.15;
H,7.98; N,3.51. Found: C,75.13; H,7.76; N,3.54. (Mass Spec.) FAB:
Found 394; Calcd. 394.
Example 20
17-.beta.-(3,5-dimethyl-4-hydroxybenzoyl)-4-aza-5.alpha.-androst-1-ene-3-on
A. Preparation of Grignard Reagent
To a suspension of 260.0 mg of dry activated magnesium chips in 6.0
ml of dry THF was added 628.0 mg of
1-bromo-3,5-dimethyl-4-tertiary-butyl-dimethylsilyloxybenzene
(prepared from 4-bromo-2,6-dimethylphenol by the General Procedure
described above) in 4.0 ml of THF/N.sub.2. The reaction was
conducted in an ultrasonic bath at a temperature range of
24.degree. C.-30.degree. C. To the well-agitated mixture was added
dropwise 40 .mu.l of 1,2-dibromoethane/N.sub.2. The reaction was
allowed to proceed for 2 hours/N.sub.2. The concentration of the
Grignard reagent thus formed was 2 mmoles in 10.0 ml of dry
THF.
The steroid from Example 2 (205.0 mg (0.5 mmoles) was suspended in
3.0 ml of dry THF, cooled to -80.degree. C., and 7.5 ml (1.50
millieq.) of the above-prepared Grignard was introduced via syringe
to the steroidal suspension over a period of 5-10 minutes/N.sub.2.
The reaction was allowed to proceed for 1 hour at -80.degree.
C./N.sub.2 and then at -10.degree. C. for additional
hour/N.sub.2.
The reaction was quenched with 1N HCl, and then diluted with
chloroform. The organic layers were combined, washed 3 times with
H.sub.2 O, 3 times with saturated sodium chloride and dried over
MgSO.sub.4, filtered and concentrated in vacuo. The crude residue
was washed with ether to afford 121.7 mg of product.
The crude product was dissolved in 70:30 (CHCl.sub.3 -acetone),
filtered through Teflon (Acrodisc CR) and purified by preparative
HPLC (Waters Prep-pak) on silica gel and eluted with 70:30
(CHCl.sub.3 -acetone).
The major component was recrystallized from ethyl acetate to give
52.0 mg of product m.pt 245-245.5.degree. C.
Anal. Calcd. for C.sub.33 H.sub.49 O.sub.3 NSi: C,73.96; H,9.23;
N,2.61; Found: C,74.06; H,9.33: N,2.64; (Mass Spec.) FAB: Found:
536; Calc.: 536
B. Deblocking the Silyl Derivative
Dissolved 54.0 mg of the above product from A in dry THF (1.3 ml).
The clear solution was cooled to 0.degree. C., and 29 .mu.l of
glacial HOAc was added via syringe/N.sub.2. To the above solution
was added dropwise 172 .mu.l of tetra-n-butylammonium fluoride at
0.degree. C. dropwise via syringe/N.sub.2. Allowed the reaction to
proceed at 0.degree. C./N.sub.2 for 11/2 hours. The reaction
mixture was poured into ice/saturated NaHCO.sub.3 solution and
EtOAc. Stirred for several minutes. Allow the layers to separate,
and the H.sub.2 O layer was extracted 3 times with EtOAc and 3
times with CHCl.sub.3.
Combined the organic layers and washed 3 times with H.sub.2 O, then
3 times with saturated NaCl, and then dried over MgSO.sub.4,
filtered and evaporated to dryness in vacuum to afford 52.2 mg.
The product was crystallized from EtOAc to give 22.5 mg of the
above-titled product m.pt 305-306.degree. C.
Calc. for C.sub.27 H.sub.35 O.sub.3 N.H.sub.2 O: C, 73.77; H, 8.49;
N, 3.10. Found: C, 73.62; H, 7.90; N, 3.44. (Mass Spec.) FAB: Calc:
422; Found: 422
Example 21
Synthesis of
17-.beta.-(4-Methoxybenzoyl)-4-aza-5-.alpha.-androst-1-ene-3-one
A. Grignard Reaction
To a suspension of 258.0 mg of dry activated Mg chips in 8.0 ml of
THF/N.sub.2 was added 748.0 mg p-bromoanisole in 2.0 ml of dry THF.
The reaction was run in an ultrasonic bath at a temperature range
of 24-30.degree. C./N.sub.2. To the well-agitated mixture was added
dropwise 30.0 .mu.l of 1,2-dibromoethane as a catalyst. The
reaction was allowed to progress for 1-2 hours at 28.degree. C. The
formed Grignard reagent had a concentration of 4 mmoles in 10.0
.mu.l of dry THF.
The steroid from Example 2 (205.0 mg (0.50 mml) was suspended in
2.0 ml of THF, cooled to -78.degree. C. and the above-prepared
Grignard reagent (3.75 ml; 14 milliequivalents) was added via
syringe to the steroidal suspension over 5-10 minutes/N.sub.2 and
then at -10.degree. C. for an additional hour/N.sub.2. The
resulting reaction mixture was a clear solution, which was cooled
to 0-5.degree. C., diluted with chloroform and quenched with 1N HCl
acid. The organic layers were separated, washed with H.sub.2 O 2
times, followed with saturated NaCl solution, dried over
MgSO.sub.4, filtered and evaporated in vacuo. The crude product was
washed with ether, and crystallized from EtOAc to give 110 mg of
product m.pt 305-306.degree. C.
Further purification was carried out by chromatographic isolation
on a TLC. plate, (20 cm.times.20 cm.times.1000 .mu.m), using as
eluant, 70:30 (CHCl.sub.3 : acetone). Recrystallization from EtOAc
yielded 78.56 mg of the above-titled product, m.pt 305-306.degree.
C. (dec.).
(Mass Spec) FAB: Calcd.,408; Found 408.
Example 22
Synthesis of
17-.beta.-(3-hydroxybenzoyl)-4-aza-5.alpha.-androst-1-ene-3 one
A. Preparation of Grignard Reagent
To a suspension of 230.0 mg of dry activated Mg chips in 2.0 ml of
dry THF was added 722.4 mg of 1-bromo-3-tertiary-butyl
dimethyl-silyloxybenzene (prepared from 3-bromophenol by the
General Procedure described above) in 8.0 ml of dry THF/N.sub.2.
The reaction was run in an ultrasonic bath at a temperature range
of 24-30.degree. C./N.sub.2. To the well-agitated mixture was added
dropwise 20.0 .mu.l of 1,2-dibromoethane/N.sub.2. Allowed the
reaction to progress for 21/2 hours at 28.degree. C./N.sub.2. The
formed Grignard reagent had a concentration of 2.52 mmoles in 10.0
ml of dry THF.
The steroid from Example 2 (205.0 mg (0.5 mmoles) was suspended in
2.0 ml of THF, cooled to -78.degree. C. and the above-prepared
Grignard reagent (6.0 ml, (1.5 milliequivalents) was added via
syringe to the steroidal suspension over 5-10 minutes/N.sub.2, and
then stirred for an additional hour at -10.degree. C./N.sub.2. The
clear reaction mixture was quenched at 0 to -5.degree. C. with 1N
HCl acid for 10.0 minutes and diluted with CHCl.sub.3. The combined
organic layers were washed 3 times with H.sub.2 O, 3 times with
saturated NaCl, and then dried over MgSO.sub.4, filtered and
concentrated in vacuo to afford crude product. The product was
purified on silica gel column and was eluted with 70:30 (CHCl.sub.3
-acetone). The desired product amounted to 58.0 mg, as the silyl
derivative,
17.beta.-(3-tertiary-butyldimethylsilyloxybenzoyl)-4-methyl-4-aza-5.alpha.
-androst-1-en-3-one.
B. Deblocking
57.6 mg of the above silyl derivative was dissolved in 3.0 ml of
dry THF. The solution was cooled to 0.degree. C., and 20 .mu.l of
glacial acetic acid was introduced via syringe. To the clear
solution was added 130.0 .mu.l of (n-butyl).sub.4 NF via syringe,
and allowed the reaction to proceed for 1 hour/N.sub.2 at 0.degree.
C. The reaction mixture was poured into EtOAc/NaHCO.sub.3 sat.
solution @ 0.degree. C. The water layer was separated, extracted 3
times with EtOAc and then 3 times with chloroform. The organic
layers were combined and washed 3 times with H.sub.2 O, 3 times
with saturated NaCl solution, dried over MgSO.sub.4, filtered and
evaporated in vacuo to give 57.11 mg of crude product. The crude
product was chromatographed by TLC (one plate, 20 cm.times.20
cm.times.250 .mu.m silica gel), eluted with 70:30 (CHCl.sub.3
-acetone) to afford 44.5 mg of the above-titled product.
Recrystallization from EtOAc gave 29.30 mg m.pt 279-280.degree.
C.
Anal. Calcl. for C.sub.25 H.sub.31 NO.sub.3 : 8H.sub.2 O: C,73.60;
H,8.06; N,3.43. Found: C,73.26; H,8.22; N,3.28. (Mass Spec.) FAB:
Calcd: 394; Found 394.
Example 23
Synthesis of
17-.beta.-(4-hydroxymethyl-benzoyl)-4-aza-5.alpha.-androst-1-en-3-one
A. Preparation of Grignard solution
To a suspension of 100.0 mg (4 mmoles) of dry activated Mg chips in
5.0 ml of dry THF/N.sub.2, was added 753.0 mg (2.5 moles) of
1-bromo-4-tertiary-butyl dimethyl silyloxy methyl benzene (prepared
from 4-bromobenzyl alcohol by the General Procedure described
above). The reaction was conducted in an ultrasonic bath at a
temperature range of 24-30.degree. C./N.sub.2. To the well-agitated
mixture was added 20 .mu.l of 1,2-dibromoethane/N.sub.2. Allowed
the reaction to progress for 2 hours at 28.degree. C./N.sub.2. The
concentration of formed Grignard was 2.5 mmoles in 5.0 ml of dry
THF.
B. Grignard Reaction
The steroid from Example 2 (205.0 mg (0.5 mmoles) was suspended in
2.0 ml of THF, cooled to -78.degree. C., and the above-prepared
Grignard (3.0 ml, 3.75 milliequivalents) was introduced via syringe
into the steroidal suspension over 5-10 minutes/N.sub.2. Allowed
the reaction to progress for 1 hour at -80.degree. C./N.sub.2, and
then for an additional hour at -10.degree. C./N.sub.2. The clear
reaction solution was quenched with saturated NH.sub.4 Cl at
0.degree. to -5.degree. C., and then diluted with CH.sub.2
Cl.sub.2. The organic layers were separated and washed 3 times with
water, 3 times with saturated NaCl, dried over MgSO.sub.4, filtered
and evaporated in vacuo to dryness. Crude product was crystallized
from EtOAc to give 137.8 mg of silyl product.
(Mass Spec.) FAB: Calcd for C.sub.30 H.sub.41 O.sub.3 NSi: 521.75
Found: 522.0.
C. Deblocking of Silyl Derivative
The product from Step B above (23.67 mg) was dissolved in 0.5 ml of
THF and 0.5 ml of MeOH and cooled to 0.degree. C./N.sub.2. To the
cold solution was added 10 .mu.l of concentrated sulfuric acid
(98%). The reaction was stirred for 45 minutes at 0.degree.
C./N.sub.2. To the cold solution at 0.degree. C. was slowly added a
saturated solution of NaHCO.sub.3 and chloroform. Extracted 3 times
with CHCl.sub.3. The organic layers were washed 3 times with water,
3 times with saturated NaCl, solution dried over MgSO.sub.4,
filtered and evaporated to dryness in vacuo, to afford 10.18 mg.
After chromatography on a TLC plate (elution with 1:1 CHCl.sub.2 :
acetone) The crude product was crystallized from EtOAc to give 6.0
mg of the above-titled product, m.pt 318-320.degree. C.
Anal. Calcd. for C.sub.26 H.sub.33 O.sub.3 N.1/3H.sub.2 O: C,75.41:
H,7.94; N,3.38. Found: C,75.61; H,7.84; N,3.12. (Mass Spec.) FAB:
Calc.: 408; Found: 408
Example 24
Synthesis of
17-.beta.-(4-Carboxybenzoyl)-4-aza-5.alpha.-androst-1-en-3-one
A. Oxidation
90.2 mg of the product from Example 23 was dissolved in 2.63 ml of
glacial acetic acid and to the clear solution was added 69.0 mg of
CrO.sub.3 (previously dried over P.sub.2 O.sub.5 at R.T. for 2 days
in vacuo). After stirring overnight, the reaction mixture was
diluted with water and allowed to age overnight in the
refrigerator. The reaction mixture was filtered and the mother
liquor and washes were extracted overnight using a liquid-liquid
extractor, (H.sub.2 O-EtOAc) under reflux conditions. The organic
layer was dried over MgSO.sub.4, filtered and evaporated in vacuo.
The residue was dissolved in hot MeOH, filtered and evaporated in
vacuo to afford a product weighing 32.0 mg.
FAB: Calc. for C.sub.26 H.sub.31 O.sub.4 N: 422.0; Found: 422.
B. Purification
The above free acid was purified by dissolving the above product in
1N sodium hydroxide solution. The clear solution was extracted 3
times with EtOAc. The aqueous basic solution was cooled and
acidified with 1N HCl acid dropwise to pH=4 with stirring. The
reaction mixture was allowed to age for 1 hour at 0.degree. C. It
was. filtered and the residue was washed with cold water. Dried
overnight to 100.degree. C. in vacuum <0.2 mm pressure.
Yield of the above-titled free acid was 9.85 mg. FAB: Calc. for
C.sub.25 H.sub.31 O.sub.4 N: 422; Found 422. NMR analysis indicated
the product to be an acid.
C. Sodium Salt of Above Acid
4.9 mg of the above product acid B was dissolved in 2.0 ml of hot
methanol. To the clear solution, was added 11.6 .mu.l of 1N
NaOH(aq). To solution after methanol evaporation in vacuo, was
added water to reach pH 7.21. The aqueous solution was freeze dried
to give 6.3 mg of the sodium salt of the above-titled product.
Example 25
Synthesis of
17-.beta.-(4-hydroxyethylbenzoyl)-4-aza-5.alpha.-androst-1-en-3-one
A. Grignard Reagent
To a suspension of 252 mg of dry activated Mg chips in 10.0 ml of
dry THF was added 1.26 g (4 mmoles) of 1-bromo-4 tertiary-butyl
dimethyl silyloxy ethyl benzene (prepared from 2-(p-bromophenyl)
ethanol by the General Procedure described above). The reaction
mixture was vigorously stirred using an ultrasonic
vibrator/N.sub.2. To the well-agitated mixture was added 40 .mu.l
of 1,2-dibromoethane to catalyze the above reaction. Allowed the
reaction to progress for 31/2-4 hours/N.sub.2. The concentration of
formed Grignard reagent was 4 mmoles in 10 ml of THF.
B. Grignard Reaction
205.0 mg (0.5 mmoles) of the aza-steroid of Example 2 was suspended
in 2.0 ml of dry THF/N.sub.2, cooled to -80.degree. C., and the
above-prepared Grignard (3.75 ml, 1.5 milliequivalents) via syringe
was introduced into the steroidal suspension over 5-10
minutes/N.sub.2. The reaction was run at -80.degree. C. for 1
hour/N.sub.2 and then for an additional hour at -10.degree. C. The
reaction was quenched with a saturated solution of NH.sub.4 Cl at
0-5.degree. C. and diluted with 10.0 ml of CH.sub.2 Cl.sub.2. The
organic layers were washed with water (3 times), saturated NaCl
solution (3 times), dried with MgSO.sub.4, filtered and evaporated
in vacuo to dryness. The crude product was crystallized from EtOAc
overnight to give 152.0 mg of product m.pt. 233-234.degree. C.
Anal. Calcd. for C.sub.33 H.sub.49 O.sub.3 NSi:1/4 H.sub.2 O:
C,73.55; H,9.18, N,2.59. Found: C,73.45; H,8.94; N,3.21 FAB: Calc.
536; Found: 536
C. Desilylation
70.8 mg of product from Step B, was dissolved in 1.45 ml of
methanol and 1.45 ml of THF. The solution was cooled to 0-5.degree.
C. and 29 .mu.l of conc. H.sub.2 SO.sub.4 was added via syringe
under N.sub.2. The reaction was allowed to proceed for 45
minutes/N.sub.2. The reaction was carefully quenched at 0.degree.
C. with a saturated solution of NaHCO.sub.3, and extracted 3 times
with CH.sub.2 Cl.sub.2. The organic layers were separated, washed
with water (3 times), then with saturated NaCl solution, dried over
MgSO.sub.4, filtered and evaporated in vacuo to give 43.0 mg of
crude product. The crude product was placed on a column of silica
gel and was eluted with 1:1 acetone-CH.sub.2 Cl.sub.2. The isolated
product was crystallized from anhydrous methanol to afford 20.0 mg
of the above-titled product m.pt 292-293.degree. C. with dec.
Anal. Calcd. for C.sub.27 H.sub.35 O.sub.3 N.1/4 H.sub.2 : C,75.31;
H,8.25; N,3.25. Found: C,75.49; H,8.29; N,3.45. FAB: Calcd 422;
Found 422.
Example 26
Synthesis of
17-.beta.-(4-carboxymethylbenzoyl)-4-aza-5.alpha.-androst-1-en-3-one
A. Oxidation
13.0 mg of the product from Example 25 was dissolved in 1 ml of
glacial acetic acid. To the clear solution was added 10.0 mg of
CrO.sub.3 (previously dried over P.sub.2 O.sub.5 in vacuum at
R.T.). Allowed the reaction to progress overnight at R.T., and then
at 0.degree. C. for 48 hours. The addition of 7.0 ml of water
caused the product to crystallize overnight in a refrigerator. The
crude product was isolated, washed with cold water and dried in a
vacuum at 110.degree. C. below 1 mm pressure.
The dried crude product was dissolved in IN sodium hydroxide and
the basic solution was extracted 3 times with methylene chloride
(The organic layers were separated, and the aqueous basic solution
was cooled and acidified with 1.5 N hydrochloric acid. The
precipitate was filtered, washed with water dried at 110.degree. C.
under vacuum at 0.1 mm pressure.
Yield of above-titled product=7.0 mg. FAB Calc. C.sub.27 H.sub.33
O.sub.4 N: 436; Found 436.
Example 27
Synthesis of
17-.beta.-(3,4-dihydroxybenzoyl)-4-aza-5.alpha.-androst-1-en-3-one
A. Grignard
To a suspension of 258.5 mg of dry activated magnesium chips in
10.0 ml of dry THF, was added 482 mg. of
4-bromo-1,2-methylenedioxybenzene/N.sub.2. (The starting material
is commercially available from Aldrich Chemical) The reaction was
conducted in an ultrasonic water bath at a temperature range of
24.degree.-30.degree. C. To the well-agitated mixture was added 40
.mu.l of 1,2-dibromoethane as a catalyst/N.sub.2, and the reaction
was allowed to progress for 11/2-2 hours at 28.degree. C./N.sub.2.
The concentration of the formed Grignard reagent was 3.75 mmoles in
10 ml of dry THF.
The steroid from Example 2 (410 mg, 1 mmole) was suspended in 4.0
ml of dry THF/N.sub.2 and cooled to -80.degree. C. and 8.0 ml of
the above-prepared Grignard (3.04 milliequivalents) was added via
syringe to the steroidal suspension/N.sub.2 over a period of 5-10
minutes. The reaction was allowed to proceed for 1 hour at
-80.degree. C., and then at -10.degree. C. for an additional
hour/N.sub.2. The reaction mixture was diluted with CH.sub.2
Cl.sub.2, and then quenched with 1N HCl at -5.degree. C.
The organic layers were collected and washed with water 3 times,
saturated NaCl solution 3 times, dried over MgSO.sub.4, filtered
and evaporated in vacuo to dryness. Purification of the crude
product was carried out on 50.0 g of silica gel using as eluant
1:1(CH.sub.2 Cl.sub.2 -acetone) to give 347.0 mg. FAB showed 422;
Calcd. 422.
62.4 mg of the above product was crystallized from EtOAc to afford
11.39 mg of product m.pt.324-325.degree. C.
Anal. Calcd. for C.sub.26 H.sub.31 O.sub.4 N.3/4 H.sub.2 O:
C,71.78; H,7.53; N,3.22. Found: C,71.90; H,7.54; N,3.25. FAB for
C.sub.26 H.sub.31 O.sub.4 N showed 422; Calcd: 422.
B. Cleavage of Methylene Dioxylan Group
70.0 mg of the product from Step A was dissolved in dry 25.0 ml of
1,2-dichloroethane at R.T./N.sub.2. The solution was allowed to
cool to -10.degree. C., and 1.03 ml of BBr.sub.3 (1.0 M solution in
dichloromethane) was added dropwise under N.sub.2 atmosphere. The
reaction was allowed to proceed at R.T. for 31/2-4 hours/N.sub.2.
After 4 hours/N.sub.2, the reaction was cooled to (-10.degree. C.)
and quenched with 10.0 ml of methanol for 10 minutes at 0.degree.
C., and then gradually the temperature was allowed to rise to
R.T./N.sub.2. The reaction mixture was evaporated in vacuo to
dryness. The residue was extracted 3 times with EtOAc. The organic
layers were washed with water 3 times, 2 times with saturated
NaHCO.sub.3 solution, 3 times with water and finally with a
saturated solution of NaCl. The organic layers were dried over
magnesium sulfate, filtered and concentrated in vacuo. The crude
material was chromatographed on 2 silica gel plates, (20
cm.times.20 cm.times.20 cm.times.250 .mu.m) eluted with 1:1
(acetone-methylene chloride). Recrystallization from EtOAc afforded
5.0 mg of the above-titled product m.p. 222-222.5.degree. C.
Anal. Calcd. for C.sub.25 H.sub.31 O.sub.4 N.1/2 H.sub.2 O:
C,71.78; H,7.66; N,3.35. Found: C,71.71; E,7.71; N,3.33. FAB:
Calcd. for C.sub.25 H.sub.31 O.sub.4 N: 410; Found 410.
Example 28
Synthesis of 17-.beta.-(2
methoxybenzoyl)-4-aza-5.alpha.-androst-1-ene-3-one
A. Grignard
To a suspension of 258.0 mg of dry activated magnesium chips in 8.0
ml of dry THF was added 771.0 mg of o-bromoanisole in 2.0 ml of dry
THF/N.sub.2. The reaction was conducted in an ultrasonic water bath
at a temperature range of 24-30.degree. C. To the well-agitated
mixture was added 30 .mu.l of 1,2-dibromoethane/N.sub.2, and the
reaction was allowed to progress for 2 hours at 28.degree.
C./N.sub.2. The concentration of the formed Grignard reagent was 4
mmoles in 10.0 ml of dry THF.
The steroid from Example 2 (205 mg, 0.5 mmoles) was suspended in
2.0 ml of dry THF/N.sub.2, cooled to -79.degree. C., and 4.0 ml of
the above-prepared Grignard (1.6 milli-equivalents) was added via
syringe to the steroidal suspension/N.sub.2 over a period of 5-10
minutes. The reaction mixture was allowed to proceed for 1 hour at
-80.degree. C., and then at 0-2.degree. C. for an additional
hour/N.sub.2. The reaction mixture was diluted with CH.sub.2
Cl.sub.2 and then quenched with 1N HCl solution at 0.degree. C.
The organic layers were combined, washed 3 times with water, 3
times with saturated NaCl solution; and dried over MgSO.sub.4.
Filtered and evaporated in vacuum to dryness. The crude material
was crystallized from EtOAc to give 124.5 mg of product m.pt
228-230.degree. C. Purification on silica gel column using 70:30
(CHCl.sub.3 -acetone) gave a single spot material in a yield of
83.0 mg m.pt. 241-241.5.
Anal. Calcd. for C.sub.26 H.sub.33 O.sub.3 N: C,76.91; H,8.19;
N,3.45 Found: C,76.36; H,8.26; N,3.35. FAB calcd. for C.sub.26
H.sub.33 O.sub.3 N: 406; Found: 406.
B. Cleavage of Methoxy Group
12.7 mg (0.03 mmoles) of the product from Step A was dissolved in
5.0 ml of dry methylene chloride/N.sub.2. To clear solution at
-79.degree. C./N, was added 50 .mu.l of 1 mmole/ml of BBr.sub.3 in
CH.sub.2 Cl.sub.2 via syringe dropwise. Allowed the reaction to
proceed at R.T. overnight/N.sub.2 with rapid stirring. Next day, a
clear yellow solution was obtained. The reaction mixture was cooled
to 0-2.degree. C. and quenched with water, to hydrolyze excess of
BBr.sub.3. The organic phase was washed 3 times with dilute sodium
hydroxide, 3 times with water, 3 times with dilute HCl, 3 times
with water, 3 times with saturated NaCl solution, and dried the
organic layer over MgSO.sub.4. Filtered, concentrated in a vacuum
to dryness. The crude product crystallized from EtOAc to afford 7.0
mg of a pure single spot material being
17-.beta.-(2-hydroxymethyl-benzoyl)-4-aza-5-.alpha.-androst-1-en-3-one.
FAB for C.sub.25 H.sub.31 NO.sub.2 ; Calcd: 394; Found: 394.
Example 29
17.beta.(.alpha.-hydroxybenzyl)-4-aza-5.alpha.-androst-1-ene-3-one
570 milligrams of
17.beta.-benzoyl-4-aza-5.alpha.-androst-1-ene-3-one (prepared from
the thiopyridyl ester of Example 2 and commercially available
phenyl magnesium bromide, analogously via the procedure in Example
5, to produce the 17-benzoyl derivative, mp. 295-296.degree. C.
crystallized from EtOAc) was suspended in 80 ml of anhydrous
isopropanol. To the suspension was added 500.0 mg of NaBH.sub.4 in
5 portions. When all the hydride was added, 20.0 ml of dry THF was
carefully added, so that the reaction mixture became a clear
solution. Allowed the reaction to proceed at R.T./N.sub.2
overnight. The reaction was quenched carefully with 1N HCl, and
allowed to stir under N.sub.2 for an additional hour at R.T. It was
then diluted with water, and extracted 3 times with CHCl.sub.3. The
organic layers were combined, washed 3 times with H.sub.2 O; 3
times with saturated NaCl solution, and dried over MgSO.sub.4.
Filtered and evaporated to a white solid weighing 495.0 mg.
The crude material was crystallized from EtOAc to afford 349.5 mg
of material. Further purification on a silica gel column, using as
eluant, 70:30 (CHCl.sub.3 -acetone) gave a single spot material,
221 mg, of the above-titled compound, m.pt 296-297.degree. C.
Anal. Calcd. for C.sub.25 H.sub.33 NO.sub.2 : C,79.17; H,8.78;
N,3.70. Found: C,79.24; H,8.85; N,3.48. FAB Calcd. for C.sub.25
H.sub.33 NO.sub.2 : 380; Found: 380.
Example 30
17.beta.-hydroxymethyl-4aza-5.alpha.-androst-1-ene-3-one
500.0 mg of S-2-pyridyl-3-oxo-4-aza-5.alpha.-androst-1-ene-3 one
(Example 2) was dissolved in 40.0 ml of dry THF at R.T./N.sub.2.
The solution was cooled to -78.degree. C./N.sub.2 and 5.5 ml of 1 M
dibutyl aluminium hydride in THF was slowly added via syringe to
the solution, with rapid stirring. Allowed the reaction to proceed
at -76 to -78.degree. C. for half an hour under N.sub.2. The
temperature was gradually brought to R.T. and the reaction mixture
kept for 2-1/2 hours/N.sub.2. The reaction was then quenched at
0.degree. to 5.degree. C. with 2N HCl acid, and then diluted with
CHCl.sub.3. The organic layers were separated, washed with H.sub.2
O 3 times, then with saturated NaCl solution, and finally dried
over MgSO.sub.2. Filtered, and the organic phase was evaporated
under vacuum to give 216.0 mg of crude product.
The crude product was chromatographed on 20.0 g of E.M. silica gel
column, using 70:30(CHCl.sub.3 -acetone) as eluant.
Yield of single spot material was 126.3 mg of the above-titled
compound, m.pt. 271-271.5.degree. C.
Calcd. for C.sub.19 H.sub.29 O.sub.2 N: FAB 304; Found 304. NMR in
CDCl.sub.3 confirmed the above structure.
Example 31
17.beta.-Formyl-4-aza-5.alpha.-androst-1-ene-3-one
Into a 100.0 ml dry flask was placed 1.3 ml of oxalyl chloride (2 M
in CH.sub.2 Cl.sub.2) with 50.0 ml of dry CH.sub.2 Cl.sub.2
/N.sub.2. The above solution was cooled to -78.degree. C. and 338
.mu.l of DMSO was added dropwise via syringe/N.sub.2. The mixture
was stirred at -78.degree. C./N.sub.2 for 30 minutes, and a
solution of above-prepared alcohol from Example 15, i.e. 17.beta.
hydroxymethyl-4-aza-5.alpha.-androst-1-ene-3-one (256.9 mg in 15.0
ml of dry CH.sub.2 Cl.sub.2 /N.sub.2 was added via syringe. The
reaction was allowed to progress for one hour at -78.degree.
C./N.sub.2. After an hour at -78.degree. C., was added 1 ml of dry
triethylamine at a rapid rate. Reaction was raised slowly to
R.T./N.sub.2 with stirring, the resulting yellow solution was then
poured into 50.0 ml of cold water. The organic layers were washed
with a saturated solution of NaHCO.sub.3, and then with a saturated
solution of NaCl. Dried over MgSO.sub.4, evaporated the solvent
under vacuum to give 172.4 mg of crude product. The crude product
was chromatographed on 60.0 g silica gel column using 70.30
(CHCl.sub.3 -acetone), to give a single spot material.
Crystallization from EtOAc afforded the above-titled compound, 37.7
mg, m.pt. 258-259.degree. C.
Example 32
Synthesis of diastereoisomeric
17.beta.(.alpha.-hydroxybenzyl)-4-aza-5.alpha.-androst-1-ene-3-ones
26.3 of above-prepared formyl derivative from Example 31) was
dissolved in 7.0 ml of dry THF/N.sub.2. The solution was cooled to
-78.degree. C./N.sub.2, and 131 .mu.l of phenyl magnesium bromide
(Aldrich reagent) 0.393 milliequivalents) in dry THF was added
dropwise via syringe/N.sub.2. Allowed the reaction to proceed for 1
hour/N.sub.2 at -78.degree. C. and then at R.T. for addition
hour/N.sub.2.
The reaction was quenched at 0-5.degree. C. with 2.5N HCl, and then
diluted with CHCl.sub.3. Organic layers were separated, washed 3
times with water; 3 times with saturated NaCl solution, dried over
MgSO.sub.4. Filtered and evaporated in vacuum to dryness to afford
28.6 mg of crude product. Analysis of the NMR spectra and peak
heights from HPLC indicated this product to be a 1:1 mixture of
diastereoisomers. The crude product was filtered through a 1 .mu.m
Teflon filter and purified by HPLC on a Whitman Portisil 10 column
using 70:30(CHCl.sub.3 -acetone). The FAB mass spectrum indicated
the same M.sup.+ +1 for both isomers, being 380 mass units. The
faster eluting isomer, m.pt. 289-289.5.degree. C., was crystallized
from EtOAc and showed a single spot material on TLC.
Anal. Calcd. for C.sub.25 H.sub.33 NO.sub.2.1/4 H.sub.2 O; C,78.39;
H,8.81; N,3.65. Found: C,78.11; H,8.65; N,3.58.
The slower eluting isomer, m.pt. 300-301.degree. C. showed a single
spot material on TLC. The faster isomer showed by NMR(CDCl.sub.3):
CH.sub.3 at C-18 was deshielded (0.89.delta.) as compared to the
slower isomer CH.sub.3 at C-18 at (0.69.delta.). The benzilic
proton for the faster isomer was also deshielded (4.5.delta.)
versus (4.95.delta.). The olefinic proton at C-1 showed deshielding
effects for the faster isomer at (6.81.delta.) to (6.62.delta.).
From the above data, the two isomers showed distinctly different
physical properties.
CHAPTER 3
Example 1
Preparation of 4-(2-(11-carboxyundecanoylamino)-phenoxy)butyric
acid
Step A: Ethyl 4-(2-nitrophenoxy)butyrate(3)
To a stirred solution of 2-nitrophenol (1.4 g, 10 mM) and ethyl
4-brombbutyrate (2.1 g, 1.57 mL, 11 mM) in 35 mL of dry acetone is
added 2 g (14.5 mM) of anhydrous, ground potassium carbonate. The
resultant colored mixture is then heated under a nitrogen
atmosphere at gentle reflux until the color due to the phenol anion
has dissipated and a yellow mixture remains. Concentration of the
cooled and filtered mixture yields an oil which on flash
chromatography (silica gel, ethyl acetate/hexane or methylene
chloride as eluant) yields 2.4 g (96% yield) of the title compound
(3) as an oily liquid. When substituted ortho-nitrophenols are used
in place of 2-nitrophenol in the above example, the corresponding
substituted 2-nitrophenoxybutyrate is obtained. Likewise, when
ethyl 4-bromobutyrate is replaced by other halo esters the
corresponding 2-nitrophenoxyalkanoate is obtained.
Step B: Ethyl 4-(2-aminophenoxy)butyrate (4)
A solution of 3 (1.27 g, 5.0 mM) in 15 mL ethyl acetate containing
200 mg of 5% palladium on carbon is reacted in a hydrogen
atmosphere (40 psig.) at room temperature until hydrogen uptake
ceases. The mixture is then filtered and concentrated in vacuo to
yield 1.0+g of (4) as an oil/low melting solid.
Step C: 12-(Isopropylthio)dodecanoic acid (6)
A mixture of 12-bromododecanoic acid (5) (0.558 g, 2.0 mM) and
sodium isopropylthiolate (1.1 g, 11.2 mM) in 1,2-dimethoxyethane
(50 mL) was deaerated (N.sub.2), heated to 85.degree. C. (bath
temperature), and kept at this temperature for 72 hours. The cooled
mixture was filtered, the collected solid dissolved in water and
filtered. The stirred solution was acidified with dilute
hydrochloric acid, aged, filtered, the solid washed well with water
and dried. There was obtained product 6 (0.54 g) as a white
solid.
When other halo-acids are used in place of 12-bromododecanoic acid
in the above example, the corresponding (isopropylthio)-acid is
obtained.
Likewise, when other mercaptan salts are used in place of sodium
isopropylthiolate in the above example, the corresponding
(alkylthio)alkanoic acids are obtained.
Representative of, but not limited to, the acids obtained by this
procedure are:
8-(Isopropylthio)octanoic acid
10-(Isopropylthio)decanoic acid
10-(Ethylthio)decanoic acid
11-(t-Butylthio)undecanoic acid
14-(n-Propylthio)tetradecanoic acid
9-(Methylthio)nonanoic acid
Step D: Ethyl
4-(2-(12-(Isopropylthio)dodecanoylamino)-phenoxy)-butyrate (7)
To a solution of (4) (0.25 g, 1.14 mM) and (6) (0.274 g, 1.0 mM) in
dry methylene chloride (10 mL) at room temperature was added
4-dimethylaminopyridine (0.122 g, 1.0 mM) followed within one
minute by a solution of N,N'-dicyclohexylcarbodiimide (0.22 g, 1.06
mM) in methylene chloride (1 mL), 3.times.1 mL rinses with
methylene chloride. After 2 days, the filtered mixture was
concentrated in vacuo and the residue flash chromatographed on
silica gel using 15-20% ethyl acetate in hexane as eluant to give
product 7 (0.22 g) as an oil that solidified readily in a short
time.
Step E 4-(2-(12-(Isopropylthio)dodecanoylamino)phenoxy)-butyric
acid (8)
A stirred solution of ester (7) (0.124 g, 0.258 mM) in methanol (10
mL) was treated at room temperature under a nitrogen atmosphere
with 2.5N sodium hydroxide solution (0.6 mL). Methanol (2.times.2
mL) was used to clear the mixture, and the reaction allowed to
continue until TLC analysis showed no ester remained. The filtered
mixture was concentrated in vacuo and the residue obtained stirred
with water (30 mL). After aging, the mixture was filtered (The cake
is the sodium salt of the product (100 mg), and the stirred
filtrate acidified with dilute hydrochloric acid, aged, filtered,
washed with water and dried to give product 8 (0.02 g) as a white
solid. M.P. 82-84.degree. C., with softening from 66.degree. C.
Treatment of 8 with NaIO.sub.4 as in Step J.sub.a will produce the
corresponding sulfoxide, and treatment of 8 with m-chloroperbenzoic
acid with Step J.sub.b will produce the corresponding sulfone.
Step F: 4-(2-(12-(Isopropylthio)dodecanoylamino)phenoxy)-butyramide
(9)
To a stirred solution of (7) (20 mg, 0.041 mM) in methanol (10 mL)
is added methanol saturated with ammonia (5 mL) and the stoppered
mixture allowed to stir at ambient temperatures until TLC analysis
shows little or no (D) remains. Concentration of the reaction
mixture followed by preparative thin layer chromatography (silica
gel; 3% methanol/methylene chloride as eluant) yields product 9 (11
mg) as a waxy solid.
Step G: Ethyl 4-(2-Amino-phenylthio)butyrate (11)
To a stirred deaerated (N.sub.2) solution of 2-aminothiophenol (10)
(1.25 g., 10 mM) and ethyl 4-bromobutyrate (2.14 g., 11 mM) in 40
mL. of dry 1,2-dimethoxyethane is added 8.3 g. of solid ground
anhydrous potassium carbonate, the resultant mixture deaerated
3.times. under nitrogen and allowed to stir at room temperature
until TLC analysis indicates the reaction is complete. The filtered
mixture is then concentrated and the residue flash chromatographed
on silica gel (85 g.) using 15% ethyl acetate/hexane as eluant to
give 1.8 g. of (11) as a pale tan oil.
Step H: Ethyl
4-(2-(10-(Isopropylthio)decanoylamino)-phenylthio)butyrate (12)
When (11) and 10-(Isopropylthio)decanoic are reacted together
analogously as per the conditions in Step (D) above, the title
compound 12 is obtained.
Step I: 4-(2-(10-(Isopropylthio)decanoylamino)phenylthio)-butyric
acid (13)
When (12) is hydrolyzed as per the conditions of Step (E) the title
compound 13 is obtained.
Step J: 4-(2-(11-(ethylsulfinyl)undecanoylamino)phenoxy)-butyric
acid
When the subject esters or acids are treated with sodium
metaperiodate (Step J.sub.a) in a suitable solvent (e.g.
acetone/water) the corresponding sulfoxides are obtained. Treatment
with meta-chloroperbenzoic acid (Step J.sub.b) yields the
corresponding sulfones. For example, when ethyl
4-(2-(11-(ethylthio)undecanoylamino)phenoxy)-butyrate 14 (0.045 g,
0.1 mM) in acetone (10 mL) is reacted with sodium metaperiodate
(0.072 g, 0.33 mM) in water (2 mL) at room temperature the
corresponding sulfoxide 15 is obtained. Hydrolysis as per Step (E)
yields product 16 as an off-white solid. Additionally, treatment of
14 with m-chloroperbenzoic acid will produce the sulfone 17, which
yields the acid 18 upon hydrolysis using the hydrolysis conditions
of Step E.
The method of preparing the novel compounds of the present
invention, already described above in general terms, may be further
illustrated by the following examples which should not be construed
as being limitations on the scope or spirit of the instant
invention.
Example 1
Synthesis of 4-(2-(11-Carboxyundecyloxy)phenoxy)-butyric acid (7)
##STR67## A. Ethyl 4-(2-Benzyloxyphenoxy)-butyrate (3)
To a stirred solution of 2-benzyloxyphenol (1) (4.0 g, 20 nM) and
ethyl 4-bromobutyrate (2) (5.6 g, 28.7 mM) in dried acetone (100
mL) was added anhydrous ground potassium carbonate (6.0 g, 44 mM)
and the resultant mixture heated at reflux under nitrogen until TLC
analysis showed the absence of the starting phenol. Flash
chromatography (silica gel, 15% ethyl acetate/hexane as eluant) of
the filtered and concentrated mixture yielded 3.0 g of product (3)
as a clear oil.
When the ethyl 4-bromobutyrate is replaced by halo-esters in the
above example, the corresponding ether-ester is obtained. Likewise,
when the above phenol is replaced by other substituted
2-benzyloxyphenols, the corresponding 2-substituted ethers are
obtained. Substitution of a 2-benzyloxy- or a
2-benzylthio-thiophenol for the 2-benzyloxyphenol yields the
corresponding thioether-ester.
B. Ethyl 4-(2-Hydroxyphenoxy)-butyrate (4)
A mixture of (3) (1.57 g, 5.0 mM), ethanol (50 mL), glacial acetic
acid (7 drops) and 10% palladium on carbon (0.7 g) was reacted in a
hydrogen atmosphere (40 p.s.i.) at room temperature until hydrogen
uptake ceased. Concentration of the filtered mixture yielded the
product (4) as an oil.
C. Ethyl 4-(2-11-(Carbomethoxy)undecyloxyphenoxy)butyrate (6)
When (4) (0.224 g, 1.0 mM) and methyl 12-bromododecanoate (5) (0.32
g, 1.1 mM) were reacted with potassium carbonate in acetone as per
Example (A), there was obtained product 6 (0.3 g) as a colorless
oil.
When methyl 12-bromododecanoate is replaced by other halo esters in
the above example, the corresponding diester is obtained.
D. 4-(2-(11-Carboxyundecyloxy)phenoxy)butyric acid (7)
To a stirred solution of (6) (0.102 g, 0.23 mM) in methanol (4 mL)
and water (3 drops) was added 2.5 N sodium hydroxide solution (0.55
mL, 1.37 mM) dropwise, and the resultant mixture cleared with
additional methanol (2 mL). When TLC analysis (2% methanol in
methylene chloride (10 mL) containing glacial acetic acid (4 drops)
indicated no mono- or diester remained, the methanol was removed in
vacuo, the residue stirred with water (10 mL), and the solution
filtered and acidified with 2N hydrochloric acid. Filtration of the
resultant precipitate followed by washing with water and drying
yielded product 7 (88 mg) as a white solid; M.P. collapses at
95.degree. C., all melted at 105.degree. C. (uncorr.; A.O. Spencer
Hot Stage).
Calculated for C.sub.22 H.sub.34 O.sub.6 : C. 66.98; H. 8.69.
Found: C. 67.32; H. 8.45.
Compounds (1)-(7) all had NMR and Mass Spectral data consistant
with their assigned molecular formulas.
4-(2-(11-Carboxyndecyloxy)phenylsulfinyl)butyric acid(7B)
When the subject thioethers, e.g., Compound 7A in Flow Sheet C, as
the ester or acid, are treated with sodium metaperoidate in a
suitable solvent (e.g., acetone/water) the corresponding sulfoxides
are obtained. Likewise, reaction of the subject thioethers with
m-chloroperbenzoic acid yields the corresponding sulfones. For
example, when 4-(2-(11-carboxyundecyloxy)phenylthio butyric acid 7A
(0.41 g, 1.0 mM) in acetone (25 mM) is reacted with sodium
metaperiodate (0.72 g, 3.3 mM) in water at room temperature, the
title sulfoxide 7B is obtained. When the same starting material in
methylene chloride is reacted with excess m-chlorobenzoic acid, the
corresponding sulfone is obtained.
Compounds (3)-(16) all had NMR and Mass Spectral data consistent
with their assigned molecular structures.
Example 1
Preparation of 4-(2-(11-carboxyundecanoylamino)-phenoxy)butyric
acid
Step A: Ethyl 4-(2-nitrophenoxy)butyrate (3)
To a stirred solution of 2-nitrophenol. (1) (1.4 g, 10 mM) and
ethyl 4-bromobutyrate (2.1 g, 1.57 mL, 11 mM) in 35 mL of dry
acetone is added 2 g (14.5 mM) of anhydrous, ground potassium
carbonate. The resultant colored mixture is then heated under a
nitrogen atmosphere at gentle reflux until the color due to the
phenol anion has dissipated and a yellow mixture remains.
Concentration of the cooled and filtered mixture yields an oil
which on flash chromatography (silica gel, ethyl acetate/hexane- or
methylene chloride as eluant) yields 2.4 g (96% yield) of the title
compound (3) as an oily liquid.
Step B: Ethyl 4-(2-aminophenoxy)butyrate (4)
A solution of (3) (1.27 g, 5.0 mM) in 15 mL ethyl acetate
containing 200 mg of 5% palladium on carbon is reacted in a
hydrogen atmosphere (40 psig.) at room temperature until hydrogen
uptake ceases. The mixture is then filtered and concentrated in
vacuo to yield 1.0+g of (4) as an oil/low melting solid.
Step C: Dodecanedioic acid, mono methyl ester (6)
Diethyl dodecanedioate (5) (34.4 g, 0.12 M) is reacted with barium
hydroxide octahydrate (19.2 g, 0.06 M) in methanol (240 mL) as per
the analogous procedure of Org. Syn., Coll. Vol. III. p. 635 to
yield 24.8 g of (6) as a white solid.
Step D: Dodecanedioic acid, mono methyl ester mono acid chloride
(7)
A mixture of mono acid (6) (10.0 g, 0.041 M) and thionyl chloride
(12.1 mL, 0.166 M) is refluxed for 5 hours, the excess thionyl
chloride removed in vacuo, and the residual acid chloride
repeatedly dissolved in dry benzene and concentrated until no
thionyl chloride remains to yield 10.8 g of the title compound (7)
as a waxy solid.
Step E: Ethyl
4-(2-(11-carbomethoxyundecanoylamino)-phenoxy)butyrate (8)
To a stirred, ice-cold solution of 0.89 g (4.0 mM) amine (4) and
dried triethylamine (1.2 mL) in dry ether (40 mL) is added dropwise
over ca. 4 minutes a solution of acid chloride (7) (1.04 g, 4.6 mM)
in 20 mL of dry ether. The resultant mixture is allowed to stir
cold for 20 minutes, and then at room temperature overnight. After
filtering off the triethylamine hydrochloride, the ether filtrate
is concentrated in vacuo and the residue chromatographed on an 82 g
silica gel column using 20% ethyl acetate/hexane as eluant to give
1.49 g (85%) of (8) as a waxy solid.
The ether/triethylamine in the above reaction may be replaced by
methylene chloride/pyridine with similar results. The same compound
may also be prepared via direct coupling of acid (6) with the same
amine using common coupling reagents, such as
dicyclohexylcarbodiimide/N,N-dimethylaminopyridine, and the
like.
Step F: 4-(2-(11-Carboxyundecanoylamino)phenoxy)-butyric acid
(9)
To a stirred solution of (8) (1.0 g, 2.22 mM) in methanol (100 mL)
is added 1 mL of water followed by dropwise addition of 2.5 N
sodium hydroxide solution (4.0 mL). The walls of the reaction flask
are rinsed down with 10 mL of methanol and the mixture is stirred
under a nitrogen atmosphere until TLC analysis shows no ester
(mono- or di-) remaining. The methanol is removed in vacuo, the
residue taken up in 100 mL of water, stirred for solution, filtered
(20 mL water rinses), and the stirred filtrate acidified dropwise
with 2 N hydrochloric acid. Filtration of the resultant precipitate
followed by copious water washing and drying gave 0.87 g (96%) of
(9) as a chalk-like white solid. The compound was one component by
TLC (silica gel, the eluant was 10 mL of 2% methanol in methylene
chloride containing 4 drops of glacial acetic acid). mp
128.5-130.degree. C. uncorr.
Microanalysis: Calc.: C, 64,84; H, 8.16; N, 3.44. Found: C, 64,90;
H, 8.34; N, 3.33.
Step G: Ethyl 4-(2-Amino-3-methylphenylthio)butyrate (11)
To a stirred deaerated (N.sub.2) solution of 2-aminothiophenol (10)
(1.25 g., 10 mM) and ethyl 4-bromobutyrate (2.14 g., 11 mM) in 40
mL. of dry 1,2-dimethoxyethane is added 8.3 g. of solid ground
anhydrous potassium carbonate, the resultant mixture deaerated
3.times. under nitrogen and allowed to stir at room temperature
until TLC analysis indicates the reaction is complete. The filtered
mixture is then concentrated and the residue flash chromatographed
on silica gel (85 g.) using 15% ethyl acetate/hexane as eluant to
give 1.8 g. of (11) as a pale tan oil.
Step H: 4-(2-(11-Carboxyundecanoylamino)phenylthio)butyric acid
(13)
When amine (11) is acylated with acid chloride (7) as per procedure
Step (E), and the resultant diester (ethyl
4-(2-(11-carbomethoxyundecanoylamino)phenylthio)butyrate 12 is
hydrolyzed in Step I as per procedure (F), the title compound, 13
m.p. 113.5-115.degree. C. is obtained.
The following representative compounds in this series were
additionally made by the procedures outlined above:
14) 4-(2-(9-Carboxynonanoylamino)phenoxy)butyric acid, m.p.
121.5-124.5.degree. C.
15) 4-(2-(10-Carboxydecanoylamino)phenoxy)butyric acid, m.p.
110-111.5.degree. C.
16) 4-(2-(12-Carboxydodecanoylamino)phenoxy)butyric acid, m.p.
116-119.degree. C.
17) 4-(2-(13-Carboxytridecanoylamino)phenoxy)butyric acid, m.p.
128-129.5.degree. C.
18) 4-(2-(15-Carboxypentadecanoylamino)phenoxy)butyric acid, m.p.
121-125.degree. C.
19) 5-(2-(11-Carboxyundecanoylamino)phenoxy)valeric acid, m.p.
112-113.5.degree. C.
20) 4-(2-(11-Carboxyundecanoylamino)-3-methylphenoxy)butyric acid,
m.p. 134.5-136.5.degree. C.
21) 4-(2-(11-Carboxyundecanoylamino)-4-methylphenoxy)butyric acid,
m.p. 99.5-100.5.degree. C.
22) 4-(2-(11-Carboxyundecanoylamino)-5-methylphenoxy)butryic acid,
m.p. 109.5-113.degree. C.
Step J: Benzyl 2-Nitrophenyl Ether (23)
When 2-nitrophenol (1) is reacted with benzylbromide under the
conditions of Step A the title ether (23) is obtained as a golden
oil.
Step K: Benzyl 2-Aminophenyl Ether (24)
A solution of benzyl 2-nitrophenyl ether (23) (1.15 g., 5.0 mM) in
ethanol (25 mL) saturated with anhydrous ammonia is stirred under a
hydrogen atmosphere (40 p.s.i.) with Raney Nickel (2 g.) until TLC
analysis indicates the absence of starting nitro compound. The
filtered mixture is freed of excess ammonia by bubbling in
anhydrous nitrogen. Removal of ethanol via vacuum distillation at
room temperature yields 1.0 g. of title compound (24) as a deep
colored crust, which was used as-is in the next reaction. This
compound may also be obtained via careful reduction in ethanol or
ethyl acetate using palladium on carbon as catalyst, but can be
accompanied by slight,over-reduction if not monitored.
Step L: N-Trifluoroacetyl 2-Benzyloxvaniline (25)
To a stirred, near solution of amine (24) (5.0 mM) in dry diethyl
ether (30 mL) is added anhydrous sodium carbonate (6.0 g., 57 mM)
and the resultant mixture cooled in an ice-water bath.
Trifluoroacetic anhydride (1.5 mL, 10.6 mM) is added dropwise to
this cold mixture over 2 minutes, the color changing to a yellowish
red. After 2 hours the cooling-bath is removed and the mixture
allowed to stir at ambient temperatures overnight. After filtering,
the filtrate is concentrated in vacuo and then pumped to yield 1.3
g. of the title compound (25) as a pale tan (with some
reddish-brown color around the edges) crust.
Step M: N-Methyl-2-Benzyloxyaniline (27)
A well-stirred solution of (25) (0.295 g., 1.0 mM), methyl iodide
(0.25 mL, 4.0 mM) and anhydrous acetone (5.0 ml) is set in an
oil-bath previously heated to 59.degree. C., and kept for 2
minutes. Powdered anhydrous potassium hydroxide (0.225 g., 4.0 mM)
is added all at once, and the bath temperature allowed to rise to
65.degree. C. Clumping-up of some of the KOH is observed. After 15
additional minutes, the reaction mixture is removed from the bath,
allowed to cool, and the volatiles removed. Methanol (7 mL) is
added with stirring to the residue of
N-Methyl-N-trifluoroacetyl-2-benzyloxyaniline (26) obtained,
followed by water (1 mL), and methanol (2 mL) (to wash down the
sides). After stirring overnight at ambient temperatures, the
methanol is removed in vacuo, the residue distributed between ether
and water, separated, the organic layer washed with additional
water, saturated sodium chloride solution, and dried over sodium
sulfate. Concentration of the filtered ether solution gives the
title compound (27) (0.212 g.) as an oil. NMR, MS, and TLC indicate
little, if any, dimethyl compound.
Step N: N-(11-(Carbomethoxy)undecanoyl)-N-Methyl-2-Benzyloxyaniline
(28)
To a stirred ice-cold solution of (27) (0.21 g., 1.0 mM) in dried
methylene chloride (10 mL) containing anhydrous pyridine (0.3 mL)
is added (7) (0.27 g., 1.03 mM), dissolved in 5 methylene chloride
(5 mL), dropwise over 1 minute (some methylene chloride used as a
rinse). After stirring cold for 30 minutes, the mixture is allowed
to stir at ambient temperature for completion of the reaction. The
reaction mixture is washed 1.times. with , 1N HCL, dried (Na.sub.2
SO.sub.4) and filtered. Flash chromatography (silica gel, 20% ethyl
acetate/hexane as eluant) of the residue obtained gives the title
compound (28) (0.33 g) as a colorless oil.
Step O: N-(11-(Carbomethoxy)undecanoyl)-N-Methyl-2-Hydroxy aniline
(29)
A solution of (28) (0.11 g., 0.25 mM) in methanol (11 mL)
containing 10% palladium on carbon (30 mg.) is shaken in a 40
p.s.i. hydrogen atmosphere until no (V) remained (TLC analysis).
The filtered solution was then concentrated in vacuo to give the
title compound (29), used immediately in step P.
Step P: Ethyl
4-(2-N-(11-Carbomethoxyundecanoyl)-N-(methyl)-amino)phenoxybutyrate
(30)
To a stirred solution of (29) (0.087 g., 0.25 mM) and ethyl
4-bromobutyrate (0.115 mL, 0.80 mM) in anhydrous acetone (10 mL) is
added anhydrous ground potassium carbonate (0.45 g., 3.2 mM) and
the resultant mixture heated under gentle reflux undera nitrogen
atmosphere for 24 hours. The mixture is cooled, filtered, and
concentrated, and the residue flash chromatographed (silica gel;
20% ethyl acetate/hexane eluant) to give 80 mg. of the title
compound (30) as a colorless oil.
Step Q:
4-(2-N-(11-Carboxyundecanoyl)-N-(methyl)-amino)-phenoxybutyric Acid
(31)
When (30) (0.055 g., 0.118 mM) is hydrolyzed as per its N-desmethyl
analog (Step F, supra), and the resultant oil obtained after
acidification is extracted with methylene chloride, there is
obtained the title compound (31), (51 mg.), as a colorless oil.
Step R: Ethyl 4-(2-(11-Bromoundecanoylamino)phenoxy)-butyrate
(32)
To a solution of (4) (2.60 g., 11 mM) and 11-bromoundecanoic acid
(2.65 g., 10 mM) in anhydrous methylene chloride (90 mL) is added
4-(dimethylamino)pyridine (1.22 g., 10 mM) followed by
N,N'-dicyclohexylcarbodiimide (2.3 g., 11 mM) (4.times.5 mL of
methylenechloride rinses). Precipitation of dicyclohexylurea (DCU)
begins within 4 minutes. When TLC analysis indicates the reaction
is complete, the mixture is filtered, the filtrate concentrated in
vacuo and the residue extracted with ether. The combined ether
extracts are washed 1.times. with 1N hydrochloric acid, 1.times.
saturated sodium chloride solution, dried (Na.sub.2 SO.sub.4) and
concentrated to a residue which is stirred, filtered, and
concentrated alternately with ether and methylene chloride until
all DCU is removed. Concentration of the final solution yields the
title product (32) (2.35 g.) as an oil that goes readily to a waxy
solid.
Attempted purification of an earlier run via column chromatography
(silica gel;20% ethyl acetate/hexane as eluant) gave an impure
product of greatly diminished yield.
Step S: Diethyl
10-(N-((2-(3-Carboethoxy)propyloxy)-phenyl)carboxamido)decylphosphonate
(33)
A stirred mixture of (32) (0.235 g., 0.5 mM) and triethyl phosphite
(TEP) (0.3 mL) is heated at 180.degree. C. (bath temperature) under
a nitrogen atmosphere for 8 hours, cooled, excess TEP removed in
vacuo, and the residue flash chromatographed (Silica gel; ethyl
acetate as eluant) to yield product 33 (0.13 g.) as a clear
colorless oil.
Step T:
Cleavage of the phosphonate ester (33) using bromotrimethylsilane
(procedure of J.C.S. Chem. Comm. p.739 (1979) yields
10-(N-((2-(3-(Carboethoxy)-propyloxy)phenyl
carboxamido)decylphosphonic acid (34).
Step U:
Further hydrolysis of (34) using the procedure of Example (F) above
yields the corresponding di-acid,
10-(N-((2-(3-Carboxy)propyloxy)phenyl)carboxamido)-decylphosphonic
acid (35).
Step V:
10-(N-((2-(3-Carboethoxy)propyloxy)phenyl)-carboxamido)decaneisothiouroniu
m bromide (36)
A stirred solution of (32) (0.047 g., 0.1 mM) in ethanol (2 mL) is
reacted with thiourea (0.010 g., 0.13 mM) under the same conditions
as (in Step W.). Concentration of the reaction mixture yields the
title compound (36) (contaminated with a small amount of thiourea)
which slowly solidifies in crystalline circles on standing.
Stirring with dried chloroform followed by filtration and
concentration yields the product as a thick wax.
Step W: Sodium
10-(N-((2-(3-Carboethoxy)propyloxy)-phenyl)carboxamido)decanethiosulfate
(37)
To a stirred solution of (32) (0.047 g., 0.1 mM) in ethanol (2.0
mL) is added water (10 drops, slowly) followed by sodium
thiosulfate (0.035 g., 0.14 mM), and the reaction mixture heated in
an oil-bath (bath temperature ca. 90.degree. C.) under a nitrogen
atmosphere until TLC analysis indicated no starting bromo compound.
The cooled mixture was then concentrated to remove the ethanol and
water yielding a white crust. Extraction of this crust with
chloroform, followed by filtration from inorganics, yielded product
(37) (49 mg.) as a glaze which goes with time to a waxy solid. This
product has appreciable water solubility.
Oxidation of (36) or (37) as per the analogous procedures in J. S.
Showell et al., J. Org. Chem 27 (1962) 2853 or C. Ziegler et al J.
Org. Chem. (1951) 621) yields the corresponding sulfonic acid
(38).
Step X: Ethyl 4-(2-Nitropyrid-3-yloxy)butyrate (40)
This compound was prepared from ethyl 4-bromobutyrate 2 and
2-nitro-3-pyridinol (39) via the procedure of Step (A), supra.
Following flash chromatography (silica gel; 1.5% methanol/methylene
chloride eluant) a dilute sodium bicarbonate wash of an ether
solution of the product was necessary to remove traces of starting
phenol. The product (40) was obtained in 76% yield as a pale yelow
oil.
Step Y: Ethyl 4-(2-Aminopyrid-3-yloxy)butyrate (41)
This compound was prepared via reduction of (40) as per the
procedure of step (B), above. The amine (41) was obtained as a waxy
solid.
Step Z: Ethyl
4-(2-(11-Carbomethoxyundecanoylamino)pyrid-3-yloxy)butyrate
(42)
When (41) and (7) are reacted as per the procedure of step (E),
above, the title compound (42) is obtained. Hydrolysis will yield
the corresponding di-acid
(4-(2-(11-Carboxyundecanoylamino)pyrid-3-yloxy)butyric acid
(43).
Step AA: N-(11-Carbomethoxyundecanoyl)-2-hydroxyaniline (44)
To a stirred near solution of 2-aminophenol (0.24 g, 2.2 mM) in
anhydrous methylene chloride (25 mL) was added dry pyridine (0.66
mL) and the mixture cooled in an ice-water bath. A solution of (7)
(0.525 g, 2.0 mM) in methylene chloride (2 mL) was added over 1
minute (2.times.1.5 mL methylene chloride rinses), and the mixture
allowed to stir cold. After 30 minutes the bath was removed. After
stirring overnight at ambient temperatures, the mixture was
filtered, the solvents removed in vacuo, and the residue pumped to
remove all traces of pyridine. The product, (44) was used as is in
subsequent steps.
Step BB:
4-(2-(11-Carbomethoxyundecanoylamino)phenoxy)-butyronitrile
(45)
When (44) and 4-bromobutyronitrile are reacted under the conditions
of step (A), above, (45) is obtained as a waxy solid. Conversely,
reacting (44) with ethyl 4-bromobutyrate as in step (A) yields
(8).
Step CC: 4-(2-(11-Carbomethoxyundecanoylamino)phenoxy)-butyramide
(46)
To a stirred solution of (45) (11 mg, 0.027 mM) in methylene
chloride (3 mL) is added activated manganese dioxide (100 mg) and
the resultant suspension allowed to stir stoppered at room
temperature. After a few days some additional methylene chloride
and manganese dioxide (100 mg) are added and the reaction allowed
to continue. This is repeated one additional time. When TLC
analysis shows no nitrile remains the mixture is filtered, the
catalyst washed well with fresh methylene chloride, and the
filtrate concentrated to yield the title product, (46) as a waxy
solid.
The above new isolated, purified compounds had NMR and Mass spectra
consistent with their assigned chemical structures. All melting
points were taken on an A.O. Spencer hot stage and are
uncorrected.
CHAPTER 4
Example 1
17.beta.-Benzoyl-Androst-3,5-diene-3-Carboxylic Acid
The title compound is made by reacting
17.beta.-carbomethoxy-androst-3,5-diene-3-protected carboxylic acid
in e.g., THF, with phenyl magnesium bromide under standard Grignard
conditions. Standard workup procedure yields the title. compound,
m.p.222-225.degree. C.
Reference Example 1
Synthesis of 4-(4-isobutylbenzyloxy)-2,3-dimethylbenzaldehyde
##STR68##
A mixture of 4-hydroxy-2,3-dimethylbenzaldehyde (220 mg),
4-isobutylbenzyl bromide (341 mg), potassium carbonate (1.38 g) and
ethyl methyl ketone (10 ml) was refluxed for 6 hrs. After cooling,
the reaction mixture was diluted with ethyl acetate, the solution
was washed with di1 hydrochloric acid, water, successively, dried
and evaporated. The residue was purified by column chromatography
on silica gel (hexane:EtOAc=10:1) to give the title compound (383
mg) having the following physical data:
TLC: Rf 0.48 (hexane:EtOAc=5:1); NMR: .delta.7.64 (1H, d), 7.32
(1H, d), 7.16 (1H, d), 5.12 (2H, s), 2.60 (3H, s), 2.48 (2H, d),
2.24 (3H, s), 1.94-1.80 (1H, m), 0.90 (6H, d).
Reference Example 2
Synthesis of 4-(4-isobutylbenzyloxy)-2,3-dimethylbenzoic acid
##STR69##
A solution of the aldehyde prepared in reference example 1 (380 mg)
in acetone (5 ml) was cooled with ice. To the solution, Jones'
reagent (2.67 N; 2 ml) was dropped and allowed to stand. The
solution was stirred for 1.5 hrs at room temperature. The reaction
was stopped by addition of isopropyl alcohol. The crystals
deposited were washed with hexane, dried and purified by column
chromatography on silica gel (hexane-EtOAc) to give the title
compound (328 mg) having the following physical data: TLC: Rf 0.36
(hexane:EtOAc=2:1); NMR: .delta.7.80 (1H, d), 7.33 (1H, d), 7.15
(1H, d), 6.90 (1H, d), 5.09 (2H, s), 2.58 (3H, s), 2.48 (2H, d),
2.26 (3H, s), 0.91 (6H, d).
Reference Example 3
Synthesis of
4-[2-[4-(4-isobutylbenzyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoic
acid ethyl ester ##STR70##
Oxalyl chloride (2 ml) was dropped to a solution of the carboxylic
acid prepared in reference example 2 (325 mg) in methylene chloride
(2 ml). The solution was stirred for 1 hr and evaporated. To an
ice-cooled mixture of ethyl 4-(2-aminophenoxy)-butanoate (232 mg),
pyridine (1 ml) and methylene chloride (15 ml), the above solution
was dropped. The mixture was stirred for 30 mins at the same
temperature and for 1 hr at room temperature. The reaction solution
was washed with water, dried and evaporated. The residue was
purified by column chromatography on silica gel (hexane:EtOAc=5:1)
to give the title compound (383 mg) having the following physical
data:
TLC: Rf 0.5 (hexane:EtOAc=3:1); NMR: .delta. 8.58-8.48 (1H, m),
8.05 (1H, s), 7.34 (H, d), 7.16 (1H, d), 7.08-6.96 (2H, m),
6.90-6.80 (2H, m), 5.07 (2H, s) 4.14-3.96 (4H, m), 2.49 (2H, d),
2.44 (3H, s), 1.18 (3H, t), 0.91 (6H, d).
Reference Example 4
Synthesis of
4-[2-[4-(4-isobutylbenzyloxy)-2,3-dimethylbenzoylamino]phenoxy]butanoic
acid ##STR71##
1N aq. Solution of lithium hydroxide (3 ml) was added to a solution
of the ester prepared in Reference Example 3 (380 mg) in
dimethoxyethane (8 ml). The mixture was stirred for 30 mins at
50.degree. C. After reaction, the solution was neutralized with
dil. hydrochloric acid and was extracted with ethyl acetate. The
extract was dried and evaporated. The residue obtained was
recrystallized from hexane to give the title compound (317 mg)
having the following physical data:
TLC: Rf 0.26 (hexane:EtOAc=1:1): mp: 143.degree. C.
Reference Example 5
By the similar procedure as reference examples 1, 2, 3 and 4, the
following compound was made,
4-[2-[4-[1-(4-isobutylphenyl-)ethoxy)-2,3-dimethylbenzoylamino]phenoxy]but
anoic acid, having the structural formula: ##STR72## in which the
Rf value is 0.37 (hexane:EtOAc=1:1), and the mass spectrum
exhibited m/z values of 503, 345.
Reference Example 6
(-)-4-[2-(4-[1-(4-isobutylphenyl)ethoxy]-2,3-dimethylbenzoylamino
phenoxy]butanoic acid
The compound prepared above in reference example 5, (403 mg) and
cinchonidine (2.36 g) were dissolved into acetone (70 ml) with
heating. The solution was allowed to stand to give white crystals.
The crystals were gathered by filtration and purified by
recrystallization from acetone four times. The white crystals
obtained were dissolved into chloroform. The solution was wahsed
with dil. hydrochloric acid. The oily layer was washed with water,
dried and evaporated to give the title compound having the
following physical data:
Appearance: white crystal; Optical angle of rotation: [a].sub.D
-39.6.degree. (c=1, CHCl.sub.3)
Reference Example 7
Sodium salt of
(-)-4-[2-(4-[1-(4-isobutylphenyl)-ethoxy]-2,3-dimethylbenzoylamino)phenoxy
]butanoic acid
The compound prepared in Reference Example 6 was dissolved into
methanol. The equivalent molar of an aq. Sodium hydroxide solution
was added and evaporated to give the title compound having the
following data: IR: .nu. 3050, 1750, 1580, 1560, 1510, 1445, 1260,
1090, 1020, 740 cm-1.
FORMULATION EXAMPLE
The following components are admixed in conventional method and
punched out to obtain 100 tablets each containing 50 mg of active
ingredient.
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4-[2-[4-[1-(4-isobutylphenl)ethoxy)- 5 g
2,3-dimethylbenzoylamino)phenoxy] butanoic acid Cellulose calcium
gluconate 0.2 g (disintegrating agent) Magnesium stearate 0.1 g
(lubricating agent) Microcrystaline cellulose 4.7 g
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